Condensed pyridazine compounds, their production and use

ABSTRACT

A condensed pyridazine derivative which exhibits anti-allergic activity, anti-histaminic activity and/or eosinophil chemotaxis-inhibiting activity, anti-inflammatory activity, anti-PAF (platelet-activating factor) activity, and the like, and is useful as an agent for preventing or treating asthma, allergic conjunctivitis, allergic rhinitis, urticaria, atopic dermatitis, and the like.

This application is the National Stage of International Application No.PCT/JP99/05469, filed on Oct. 5, 1999.

TECHNICAL FIELD

The present invention relates to novel condensed pyridazine derivativesexhibiting an excellent anti-allergic, anti-histaminic,anti-inflammatory or eosinophil chemotaxis-inhibiting activity, or otheractivities, and useful as agents for preventing or treating atopicdermatitis, allergic rhinitis, bronchial asthma, allergicconjunctivitis, chronic urticaria, etc., their pro-drugs, methods oftheir production, and their use in medicaments.

BACKGROUND ART

A large number of compounds with a condensed pyridazine skeleton arecurrently synthesized as drugs for a variety of diseases. For example,U.S. Pat. No. 3,915,968 discloses a compound represented by the formula:

wherein R and R³ independently represent a hydrogen atom or a loweralkyl group (at least one of R and R³ is a lower alkyl group); R¹ and R²represent a heterocyclic group selected from the group consisting ofpyrrolidine, piperidine, piperazine and morpholine taken together withthe adjacent nitrogen atom; or a salt thereof. U.S. Pat. No. 4,136,182discloses that a compound represented by the formula:

wherein R represents a hydrogen atom, a phenyl group or a loweralkylcarbonylamino group; R¹ represents morpholino or piperidino; R²represents a hydrogen atom or a lower alkyl group (at least one of R andR² is a group other than a hydrogen atom; when R is a phenyl group, R¹is morpholino and R² is a lower alkyl group); or a salt thereof, isuseful as a bronchodilator for mitigating bronchial spasms.

Also, Japanese Patent Unexamined Publication No. 279447/1994 disclosesthat a compound represented by the formula:

wherein R¹ represents a hydrogen atom, a lower alkyl group that may besubstituted, or a halogen atom; R² and R³ independently represent ahydrogen atom or a lower alkyl optionally having a substituent, or mayform a 5- to 7-membered ring with the adjacent —C═C—; X represents anoxygen atom or S(O)p (p represents an integer from 0 to 2); Y representsa group represented by the formula:

(R⁴ and R⁵ independently represent a hydrogen atom or a lower alkylgroup optionally having a substituent) or a divalent group derived froma 3- to 7-membered homocycle or heterocycle optionally having asubstituent; R⁶ and R⁷ independently represent a hydrogen atom, a loweralkyl group optionally having a substituent, a cycloalkyl groupoptionally having a substituent, or an aryl group that may besubstituted, or may form a nitrogen-containing heterocyclic groupoptionally having a substituent, with the adjacent nitrogen atom; mrepresents an integer from 0 to 4, and n represents an integer from 0 to4; or a salt thereof; and, as an example synthetic product, a compoundof the formula:

exhibits anti-asthmatic, anti-PAF, anti-inflammatory and anti-allergicactivities.

Furthermore, Japanese Patent Unexamined Publication No. 279446/1994describes a compound represented by the formula:

wherein R¹ represents a hydrogen atom, a lower alkyl group optionallyhaving a substituent, or a halogen atom; R² and R³ independentlyrepresent a hydrogen atom or a lower alkyl group optionally having asubstituent (provided that either of R² and R³ is a hydrogen atom, theother represents a lower alkyl group optionally having a substituent),or may form a 5- to 7-membered ring taken together with the adjacent—C═C—; X represents an oxygen atom or S(O)p (p represents an integerfrom 0 to 2); Y represents a group represented by the formula:

(R⁴ and R⁵ independently represent a hydrogen atom or a lower alkylgroup optionally having a substituent) or a divalent group derived froma 3- to 7-membered homocycle or heterocycle optionally having asubstituent; R⁶ and R⁷ independently represent a hydrogen atom, a loweralkyl group optionally having a substituent, a cycloalkyl groupoptionally having a substituent, or an aryl group optionally having asubstituent, or may form a nitrogen-containing heterocyclic groupoptionally having a substituent, taken together with the adjacentnitrogen atom; m represents an integer from 0 to 4, and n represents aninteger from 0 to 4; or a salt thereof; and discloses that thesecompounds possess anti-allergic, anti-inflammatory and anti-PAF(platelet activating factor) activities to suppress bronchial spasms andbronchial contraction, and can be used as effective anti-asthmaticagents.

On the other hand, as compounds possessing anti-allergic oranti-histaminic activities, there may be mentioned, for example,terfenadine (The Merck Index, 12th edition, 9307) and ebastine (TheMerck Index, 12th edition, 3534), which are already in clinical use.

In addition, EP128536 discloses anti-bacterial compounds represented bythe formula:

and so on, and U.S. Pat. No. 4,499,088 discloses anti-bacterialcompounds represented by the formula:

and so on. However, no description is given about anti-allergicactivity, anti-histaminic activity, anti-inflammatory activity and soon.

There is demand for the development of novel compounds more satisfactorythan conventional anti-allergic agents, anti-histaminic agents,anti-inflammatory agents etc. in terms of activity efficacy, sustainedactivity, safety etc.

DISCLOSURE OF THE INVENTION

After various extensive investigations to resolve the above problems,the present inventors synthesized for the first time (1) a novelcondensed pyridazine compound, owing to its unique chemical structurecharacterized by the presence of substituted piperidine or piperazinevia a spacer from the 6-position of the triazolo[4,3-b]pyridazineskeleton, or a salt thereof, and (2) a novel condensed pyridazinecompound, owing to its unique chemical structure characterized by thepresence of substituted piperidine or piperazine via a spacer from the6-position of the [1,2,4]triazolone[4,3-b]pyridazine skeleton, or a saltthereof, and found that these compounds exhibit unexpectedly excellentanti-allergic, anti-histaminic, anti-inflammatory, eosinophilchemotaxis-inhibiting activity, and excellent sustained activity andsafety, based on their unique chemical structures, and are useful aspreventive or therapeutic agents for atopic dermatitis, allergicrhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria,etc., based on these pharmacological activities. The inventors conductedfurther investigations based on these findings, and developed thepresent invention.

The present invention provides:

(1) A compound represented by the formula:

wherein Ring A is a ring represented by the formula:

(wherein R^(1a) is a hydrogen atom, a halogen atom, a hydrocarbon groupoptionally having a substituent, an acyl group or a hydroxy group havinga substituent; R^(1b) is a hydrogen atom, a halogen atom, a hydrocarbongroup optionally having a substituent, an acyl group or a hydroxy groupoptionally having a substituent); Ar¹ and Ar² are independently anaromatic group optionally having a substituent, and may form a condensedring group with an adjacent carbon atom; Ring B is a nitrogen-containingheterocycle optionally having a substituent; X and Y, whether identicalor not, are a bond, an oxygen atom, S(O)p (p is an integer from 0 to 2),NR⁴ wherein R⁴ is a hydrogen atom or a lower alkyl group, or a divalentlinear lower hydrocarbon group which may have a substituent, and whichmay contain 1 to 3 hetero atoms; R² and R³, whether identical or not,are a hydrogen atom, a halogen atom, a hydrocarbon group optionallyhaving a substituent, an acyl group or a hydroxy group optionally havinga substituent; R⁷ is a hydrogen atom, a hydroxy group which may besubstituted by lower alkyl or a carboxyl group; provided that Ring B isnot a heterocycle represented by the formula:

wherein r is 0 or 1, or a salt thereof,

(2) A compound as defined in term (1) wherein Ar¹ and Ar² areindependently an aromatic hydrocarbon group optionally having asubstituent,

(3) A compound as defined in term (1) wherein Ar¹ and Ar² areindependently a phenyl group optionally having a substituent,

(4) A compound as defined in term (1) wherein Ar¹ and Ar² areindependently

(1) a phenyl group which may be substituted by a halogen atom or C₁₋₆alkyl, or

(2) a 5- to 8-membered aromatic heterocyclic group containing 1 to 4hetero atoms selected from among a nitrogen atom, a sulfur atom and anoxygen atom, in addition to carbon atoms,

(5) A compound as defined in term (1) wherein Ring B is a ringrepresented by the formula:

wherein Z is a nitrogen atom or a methine group, Z¹ and Z² areindependently a linear C₁₋₄ alkylene group which may be substituted by ahydroxy group, an oxo group or a C₁₋₆ alkyl group,

(6) A compound as defined in term (1) wherein X is a bond, an oxygenatom or NH,

(7) A compound as defined in term (1) wherein Y is

(i) a C₁₋₆ alkylene group,

or a group represented by the formula:

(ii) —(CH₂)p O—,

(iii) —(CH₂)p¹NH—,

(iv) —(CH₂)p¹S—,

(v) —(CH₂)q¹CH(OH)(CH₂)q²O—,

(vi) —(CH₂)q¹CH(OH)(CH₂)q²NH—,

(vii) —(CH₂)q¹CH(OH)(CH₂)q²S—,

(viii) —(CH₂)p¹CONH—,

(ix) —COO(CH₂)p¹O—,

(x) —COO(CH₂)p¹NH—,

(xi) —COO(CH₂)p¹S—,

(xii) —(CH₂)q¹O(CH₂)q²O—,

(xiii) —(CH₂)q¹O(CH₂)q²NH— or

(xiv) —(CH₂)q¹O(CH₂)q²S— wherein p¹ is an integer from 1 to 6, q¹ and q²are independently an integer from 1 to 3,

(8) A compound as defined in term (1) wherein Y is a group representedby the formula:

—(CH₂)m-Y¹—(CH₂)n-Y²—

wherein Y¹ and Y² are independently a bond, an oxygen atom, S(O)p (p isan integer from 0 to 2), NR⁴ (R⁴ is a hydrogen atom or a lower alkylgroup), a carbonyl group, a carbonyloxy group or a group represented bythe formula:

wherein R⁵ and R⁶, whether identical or not, are a hydroxy group or aC₁₋₄ alkyl group; m and n are independently an integer from 0 to 4 (sumof m and n is not more than 6),

(9) A compound as defined in term (1) wherein R^(1a) is

(1) a hydrogen atom,

(2) a carboxyl group,

(3) a C₁₋₆ alkoxy-carbonyl group,

(4) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆alkoxy-carbonyl and (iv) carbamoyl, or

(5) a carbamoyl group which may be substituted by a C₁₋₆ alkyl groupoptionally having carboxyl or C₁₋₆ alkoxy-carbonyl,

(10) A compound as defined in term (1) wherein R^(1b) is

(1) a hydrogen atom, or

(2) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii)C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆alkoxy-carbonyl,

(11) A compound as defined in term (1) wherein R² and R³ are a hydrogenatom,

(12) A compound as defined in term (1) wherein R⁷ is a hydrogen atom ora hydroxy group,

(13) A compound as defined in term (1) wherein Ar¹ and Ar² areindependently a phenyl group which may be substituted; Ring B is a ringrepresented by the formula:

X is a bond or an oxygen atom;

Y is a group represented by the formula:

—(CH₂)m-Y³—(CH₂)n-Y⁴—

 wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and mand n are independently an integer from 0 to 6 (sum of m and n is notmore than 6);

R^(1a) is

(1) a hydrogen atom,

(2) a carboxyl group,

(3) a C₁₋₆ alkoxy-carbonyl group,

(4) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆alkoxy-carbonyl and (iv) carbamoyl, or

(5) a carbamoyl group which may be substituted by a C₁₋₆ alkyl groupoptionally having carboxyl or C₁₋₆ alkoxy-carbonyl;

R^(1b) is

(1) a hydrogen atom, or

(2) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii)C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆alkoxy-carbonyl;

R², R³ and R⁷ are a hydrogen atom,

(14) A compound represented by the formula:

wherein the symbols have the same definitions as those shown in term(1), or a salt thereof,

(15) A compound as defined in term (14) wherein Ar¹ and Ar² areindependently a phenyl group which may be substituted; Ring B is a ringrepresented by the formula:

X is a bond or an oxygen atom; Y is a group represented by the formula:

—(CH₂)m ¹-Y³—(CH₂)n ¹-Y⁴—

 wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and m¹and n¹ are independently an integer from 0 to 4 (sum of m¹ and n¹ is notmore than 6); R^(1a) is (1) a hydrogen atom, (2) a carboxyl group, (3) aC₁₋₆ alkoxy-carbonyl group, (4) a C₁₋₆ alkyl group which may besubstituted by a group selected from the group consisting of (i) cyano,(ii) carboxyl, (iii) C₁₋₆ alkoxy-carbonyl and (iv) carbamoyl, or (5) acarbamoyl group which may be substituted by a C₁₋₆ alkyl groupoptionally having carboxyl or C₁₋₆ alkoxy-carbonyl; and R², R³ and R⁷are a hydrogen atom,

(16) {circle around (1)}6-[6-[4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazine,

{circle around (2)}6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazine,

{circle around (3)}3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine,

{circle around (4)}6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylicacid, or a salt thereof,

(17) A compound represented by the formula:

wherein the symbols have the same meanings as defined in term (1), or asalt thereof,

(18) A compound as defined in term (17) wherein the partial structuralformula:

(wherein the symbols have the same meanings as defined in term (1))represents the formula:

(wherein the symbols have the same meanings as defined in term (1)),provided that R^(1b) is a hydrogen atom,

(19) A compound as defined in term (17) wherein Ar¹ and Ar² areindependently a phenyl group which may be substituted; Ring B is a ringrepresented by the formula:

X is an oxygen atom; Y is a group represented by the formula:

—(CH₂)w-Y⁵—

 wherein w is an integer from 1 to 6, and Y⁵ is an oxygen atom or NH;R^(1b) is

(1) a hydrogen atom, or

(2) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii)C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆alkoxy-carbonyl; and R², R³ and R⁷ are a hydrogen atom,

(20) {circle around (1)}6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one,

{circle around (2)} ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate,

{circle around (3)}2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionicacid,

{circle around (4)} 4pivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate,

{circle around (5)} pivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate,or a salt thereof,

(21) A pro-drug of a compound as defined in term (1).

(22) A method for producing a compound as defined in term (1), whichcomprises reacting a compound represented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the samemeanings as defined in term (1), or a salt thereof, with a compoundrepresented by the formula:

wherein Q² represents a leaving group; the other symbols have the samemeanings as defined in term (1), or a salt thereof,

(23) A method for producing a compound as defined in term (14), whichcomprises reacting a compound represented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the samemeanings as defined in term (1), or a salt thereof, with a compoundrepresented by the formula:

wherein Q² represents a leaving group; the other symbols have the samemeanings as defined in term (1), or a salt thereof,

(24) A method for producing a compound as defined in term (17), whichcomprises reacting a compound represented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the samemeanings as-defined in term (1), or a salt thereof, with a compoundrepresented by the formula:

wherein Q² represents a leaving group; the other symbols have the samemeanings as defined in term (1), or a salt thereof,

(25) A pharmaceutical composition containing a compound as defined interm (1) or a pro-drug as defined in term (21),

(26) A pharmaceutical composition as defined in term (25) which is ananti-histaminic and/or eosinophil chemotaxis-inhibiting agent,

(27) A pharmaceutical composition as defined in term (25) which is ananti-allergic agent,

(28) A pharmaceutical composition as defined in term (25) which is anagent for preventing or treating asthma, allergic conjunctivitis,allergic rhinitis, chronic urticaria or atopic dermatitis,

(29) A method for suppressing histamine and/or eosinophil chemotaxiscomprising administering an effective amount of a compound as defined interm (1) or a pro-drug as defined in term (21) to mammals,

(30) A method for treating allergic diseases comprising administering aneffective amount of a compound as defined in term (1) or a pro-drug asdefined in term (21) to mammals,

(31) A method for treating asthma, allergic conjunctivitis, allergicrhinitis, chronic urticaria or atopic dermatitis which comprisesadministering an effective amount of a compound as defined in term (1)or a pro-drug as defined in term (21) to mammals,

(32) Use of a compound as defined in term (1) or a pro-drug as definedin term (21) for producing an anti-histaminic and/or eosinophilchemotaxis-inhibiting agent,

(33) Use of a compound as defined in term (1) or a pro-drug as definedin term (21) for producing an anti-allergic agent, and

(34) Use of a compound as defined in term (1) or a pro-drug as definedin term (21) for producing an agent for preventing or treating asthma,allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopicdermatitis.

And, the present invention also provides:

(35) A compound as defined in term (1) wherein Ar¹ and Ar² areindependently {circle around (1)} a C₆₋₁₄ aromatic hydrocarbon group, or{circle around (2)} a 5- to 8-membered aromatic heterocyclic groupcontaining 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, in addition to carbon atoms, or {circle around(3)} a monovalent group resulting from removal of an optionally selectedhydrogen atom from a condensed ring formed by said aromatic heterocyclicgroup and C₆₋₁₄ aromatic hydrocarbon group, which C₆₋₁₄ aromatichydrocarbon group, 5- to 8-membered aromatic heterocyclic group andmonovalent group may be substituted by a group selected from the groupconsisting of (i) a halogen atom, (ii) C₁₋₆ alkylenedioxy, (iii) nitro,(iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi) optionallyhalogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl,(viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to 3halogen atoms, mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl, (x)optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii)mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or 6-memberedcyclic amino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl, (xviii) C₁₋₆alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi) di-C₁₋₆alkyl-carbamoyl or di-C₁₋₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo; and Ar¹ and Ar², along with the adjacentcarbon atom, may form a condensed cyclic group represented by theformula:

 wherein R⁷ is a hydrogen atom, a hydroxy group which may be substitutedby C₁₋₆ alkyl or a carboxyl group, which condensed cyclic group may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₆ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to 3 halogen atoms,mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or 6-membered cyclicamino, (xvi) C₁₋₆ alkylcarbonyl, (xvii) carboxyl, (xviii) C₁₋₆alkoxy-carbonyl, (xix) carbamoyl (or carbamoyl), (xx) mono-C₁₋₆alkyl-carbamoyl (or mono-C₁₋₆ alkyl-carbamoyl), (xxi) di-C₁₋₆alkyl-carbamoyl (or di-C₁₋₆ alkyl-carbamoyl), (xxii) C₆₋₁₀aryl-carbamoyl (or C₆₋₁₀ aryl-carbamoyl), (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo; the ring B is a 3- to 13-memberednitrogen-containing heterocycle which contains at least one nitrogenatom, and which may contain 1 to 3 hetero atoms selected from among anitrogen atom, an oxygen atom and a sulfur atom, which 3- to 13-memberednitrogen-containing heterocycle may be substituted by a group selectedfrom the group consisting of (i) a halogen atom, (ii) C₁₋₆alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxyoptionally having 1 to 3 halogen atoms, mono- or di-C₁₋₆ alkylamino orC₁₋₆ alkoxy-carbonyl, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C₁₋₆alkyl-carbonyl, (xvii) carboxyl, (xviii) C₁₋₆ alkoxy-carbonyl, (xix)carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆alkyl-thiocarbamoyl, (xxi) di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆alkyl-thiocarbamoyl, (xxii) C₆₋₁₀ aryl-carbamoyl or C₆₋₁₀aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆ alkylsulfonyl, (xxv)C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆ aralkyloxy and (xxviii)oxo; X and Y, whether identical or not, are {circle around (1)} a bond,{circle around (2)} an oxygen atom, {circle around (3)} S(O)p wherein pis an integer from 0 to 2, {circle around (4)} NR⁴ wherein R⁴ is ahydrogen atom or a linear or branched C₁₋₆ alkyl group or {circle around(5)} a divalent linear C₁₋₆ hydrocarbon group which may contain 1 to 3hetero atoms selected from among an oxygen atom and a sulfur atom, andwhich optionally have a substituent selected from the group consistingof (i) a halogen atom, (ii) C₁₋₆ alkylenedioxy, (iii) nitro, (iv) cyano,(v) optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to 3 halogen atoms,mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or 6-membered cyclicamino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl, (xviii) C₁₋₆alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi) di-C₁₋₆alkyl-carbamoyl or di-C₁₋₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo; R^(1a) is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, aC₃₋₆ cycloalkyl group, a condensed group formed by a C₃₋₆ cycloalkylgroup and a benzene ring optionally having 1 to 3 C₁₋₆ alkoxy groups, aC₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group, which may be substituted by agroup selected from the group consisting of (i) a halogen atom, (ii)C₁₋₆ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenatedC₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxyoptionally having 1 to 3 halogen atoms, mono- or di-C₁₋₆ alkylamino orC₁₋₆ alkoxy-carbonyl, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C₁₋₆alkyl-carbonyl, (xvii) carboxyl, (xviii) C16 alkoxy-carbonyl, (xix)carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆alkyl-thiocarbamoyl, (xxi) di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆alkyl-thiocarbamoyl, (xxii) C₆₋₁₀ aryl-carbamoyl or C₆₋₁₀aryl-thiocarbamoyl, (xxiii) sulfo; (xxiv) C₁₋₆ alkylsulfonyl, (xxv)C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆ aralkyloxy and (xxviii)oxo,

(4) an acyl group represented by the formula —(C═O)—R⁸, —SO₂—R⁸, —SO—R⁸,—(C═O)NR⁸R⁹, —(C═O)O—R⁸, —(C═S)O—R⁸ or —(C═S)NR⁸R⁹ wherein R⁸ is (a) ahydrogen atom, (b) a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆alkynyl group, a C₃₋₆ cycloalkyl group, a condensed group formed by aC₃₋₆ cycloalkyl group and a benzene ring optionally having 1 to 3 C₁₋₆alkoxy groups, a C₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group, which may besubstituted by a group selected from the group consisting of (i) ahalogen atom, (ii) C₁₋₆ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) optionally halogenated C₂₋₆ alkynyl, (viii) C₃₋₆cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to 3 halogen atoms,mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl, (x) optionallyhalogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino, (xiii) mono-C₁₋₆alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or 6-membered cyclicamino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl, (xviii) C₁₋₆alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi) di-C₁₋₆alkyl-carbamoyl or di-C₁₋₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆ararkyloxy and (xxviii) oxo, or (c) a group represented by the formula—OR¹⁰ wherein R¹⁰ is a hydrogen atom or a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, acondensed group formed by a C₃₋₆ cycloalkyl group and a benzene ringoptionally having 1 to 3 C₁₋₆ alkoxy groups, a C₆₋₁₄ aryl group or aC₇₋₁₆ aralkyl group, which may be substituted by a group selected fromthe group consisting of (i) a halogen atom, (ii) C₁₋₆ alkylenedioxy,(iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi)optionally halogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to3 halogen atoms, mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl,(x) optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino,(xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or6-membered cyclic amino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl,(xviii) C₁₋₆ alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx)mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi)di-C₁₋₆ alkyl-carbamoyl or di-C₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo, R⁹ is a hydrogen atom or a C₁₋₆ alkylgroup, or

(5) a group represented by the formula —OR¹ wherein R¹ is a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkylgroup, a condensed group formed by a C₃₋₆ cycloalkyl group and a benzenering optionally having 1 to 3 C₁₋₆ alkoxy groups, a C₆₋₁₄ aryl group ora C₇₋₁₆ aralkyl group, which may be substituted by a group selected fromthe group consisting of (i) a halogen atom, (ii) C₁₋₆ alkylenedioxy,(iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi)optionally halogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to3 halogen atoms, mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl,(x) optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino,(xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or6-membered cyclic amino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl,(xviii) C₁₋₆ alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx)mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi)di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, c(xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo;

 R^(1b), R² and R³ are independently

(1) a hydrogen atom,

(2) a halogen atom,

(3) a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, aC₃₋₆ cycloalkyl group, a condensed group formed by a C₃₋₆ cycloalkylgroup and a benzene ring optionally having 1-to 3 C₁₋₆ alkoky groups, aC₆₋₁₄ aryl group or a C₇₋₁₆ aralkyl group, which may be substituted by agroup selected from the group consisting of (i) a halogen atom, (ii)C₁₋₆ alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenatedC₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxyoptionally having 1 to 3 halogen atoms, mono- or di-C₁₋₆ alkylamino orC₁₋₆ alkoxy-carbonyl, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C₁₋₆alkyl-carbonyl, (xvii) carboxyl, (xviii) C₁₋₆ alkoxy-carbonyl, (xix)carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆alkyl-thiocarbamoyl, (xxi) di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆alkyl-thiocarbamoyl, (xxii) C₆₋₁₀ aryl-carbamoyl or C₆₋₁₀aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆ alkylsulfonyl, (xxv)C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆ aralkyloxy and (xxviii)oxo,

(4) an acyl group represented by the formula —(C═O)—R¹², —SO₂—R¹²,—SO—R¹², —(C═O)NR¹²R¹³, —(C═O)O—R¹², —(C═S)O—R¹² or —(C═S)NR¹²R¹³wherein R¹² is (a) a hydrogen atom, (b) a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, acondensed group formed by a C₃₋₆ cycloalkyl group and a benzene ringoptionally having 1 to 3 C₁₋₆ alkoxy groups, a C₆₋₁₄ aryl group or aC₇₋₁₆ aralkyl group, which may be substituted by a group selected fromthe group consisting of (i) a halogen atom, (ii) C₁₋₆ alkylenedioxy,(iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi)optionally halogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to3 halogen atoms, mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl,(x) optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino,(xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or6-membered cyclic amino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl,(xviii) C₁₋₆ alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx)mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi)di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo, or (c) a group represented by the formula—OR¹⁴ wherein R¹⁴ is a hydrogen atom, or a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group, acondensed group formed by a C₃₋₆ cycloalkyl group and a benzene ringoptionally having 1 to 3 C₁₋₆ alkoxy, a C₆₋₁₄ aryl group or a C₇₋₁₆aralkyl group, which may be substituted by a group selected from thegroup consisting of (i) a halogen atom, (ii) C₁₋₆ alkylenedioxy, (iii)nitro, (iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi)optionally halogenated C₂₋₆ alkenyl, (vii) optionally halogenated C₂₋₆alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxy optionally having 1 to3 halogen atoms, mono- or di-C₁₋₆ alkylamino or C₁₋₆ alkoxy-carbonyl,(x) optionally halogenated C₁₋₆ alkylthio, (xi) hydroxy, (xii) amino,(xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆ alkylamino, (xv) 5- or6-membered cyclic amino, (xvi) C₁₋₆ alkyl-carbonyl, (xvii) carboxyl,(xviii) C₁₋₆ alkoxy-carbonyl, (xix) carbamoyl or thiocarbamoyl, (xx)mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆ alkyl-thiocarbamoyl, (xxi)di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆ alkyl-thiocarbamoyl, (xxii) C₆₋₁₀aryl-carbamoyl or C₆₋₁₀ aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆alkylsulfonyl, (xxv) C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆aralkyloxy and (xxviii) oxo, R¹³ is a hydrogen atom or a C₁₋₆ alkylgroup; or

(5) a group represented by the formula —OR¹⁵ wherein R¹⁵ is a hydrogenatom, or a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group,a C₃₋₆ cycloalkyl group, a condensed group formed by a C₃₋₆ cycloalkylgroup and a benzene ring optionally having 1 to 3 C₁₋₆ alkoxy, a C₆₋₁₄aryl group or a C₇₋₁₆ aralkyl group, which may be substituted by a groupselected from the group consisting of (i) a halogen atom, (ii) C₁₋₆alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) optionallyhalogenated C₂₋₆ alkynyl, (viii) C₃₋₆ cycloalkyl, (ix) C₁₋₆ alkoxyoptionally having 1 to 3 halogen atoms, mono- or di-C₁₋₆ alkylamino orC₁₋₆ alkoxy-carbonyl, (x) optionally halogenated C₁₋₆ alkylthio, (xi)hydroxy, (xii) amino, (xiii) mono-C₁₋₆ alkylamino, (xiv) di-C₁₋₆alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) C₁₋₆alkyl-carbonyl, (xvii) carboxyl, (xviii) C₁₋₆ alkoxy-carbonyl, (xix)carbamoyl or thiocarbamoyl, (xx) mono-C₁₋₆ alkyl-carbamoyl or mono-C₁₋₆alkyl-thiocarbamoyl, (xxi) di-C₁₋₆ alkyl-carbamoyl or di-C₁₋₆alkyl-thiocarbamoyl, (xxii) C₆₋₁₀ aryl-carbamoyl or C₆₋₁₀aryl-thiocarbamoyl, (xxiii) sulfo, (xxiv) C₁₋₆ alkylsulfonyl, (xxv)C₆₋₁₀ aryl, (xxvi) C₆₋₁₀ aryloxy, (xxvii) C₇₋₁₆ aralkyloxy and (xxviii)oxo;

 R⁷ is a hydrogen atom, a hydroxy group which may be substituted by C₁₋₆alkyl, or a carboxyl group.

Furthermore, when Compound (I) or a salt thereof has asymmetric carbonatoms in the structure thereof, optical isomers and racemates areincluded in the scope of the present invention. Compound (I) or a saltthereof may be a hydrate or anhydrate.

BEST MODES OF EMBODIMENT OF THE INVENTION

In Formula (I) above, ring A is a ring represented by the formula:

wherein R^(1a) is a hydrogen atom, a halogen atom, a hydrocarbon groupoptionally having a substituent, an acyl group or a hydroxy group havinga substituent; R^(1b) is a hydrogen atom, a halogen atom, a hydrocarbongroup optionally having a substituent, an acyl group or a hydroxy grouphaving a substituent.

With respect to Formula (I) above, Compound (I) wherein Ring A is Type(a) and Compound (I) wherein Ring A is Type (b) are hereinafter referredto as Compound (Ia) and Compound (Ib), respectively.

In Formula (I) above, Ar¹ and Ar² are an “aromatic group optionallyhaving a substituent,” and may form a condensed ring group with anadjacent carbon atom.

Examples of the “aromatic group” represented by Ar¹ and Ar² include{circle around (1)} monocyclic or condensed polycyclic aromatichydrocarbon groups, specifically 6- to 14-membered monocylic orcondensed polycyclic aromatic hydrocarbon groups such as C₆₋₁₄ arylgroups (e.g., phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl,2-indenyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.)(preferably phenyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl,etc., particularly preferably phenyl, etc.), or {circle around (2)}monocyclic groups (preferably 5- to 8-membered) containing 1 or more(e.g., 1 to 4, preferably 1 to 3) of one or two kinds of hetero atomsselected from among a nitrogen atom, a sulfur atom and an oxygen atom,in addition to carbon atoms, or condensed aromatic heterocyclic groupsthereof, specifically aromatic heterocycles such as thiophene,benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, thianthrene,furan, indolizine, xanthrene, phenoxathin, pyrrole, imidazole, triazole,thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,indole, isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline,quinoline, phthalazine, naphthylidine, quinoxaline, quinazoline,cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine,isothiazole, phenothiazine, isoxazole, furazan, phenoxazine andisochroman (preferably pyridine, thiophene, furan, etc., more preferablypyridine etc.), or monovalent groups resulting from removal of anoptionally selected hydrogen atom from a condensed ring formed by one ofthese rings (preferably monocyclic heterocycles mentioned above) and oneor more than one (preferably 1 or 2, more preferably 1) aromatic ring(e.g., aromatic hydrocarbon groups mentioned above, preferably benzenering, etc.).

The “aromatic group” of the “aromatic group optionally having asubstituent” represented by Ar¹ and Ar² is preferably phenyl or thelike.

Examples of the “substituent” for the aromatic group represented by Ar¹and Ar² include: (i) halogen atoms (e.g., fluorine, chlorine, bromine,iodine), (ii) lower alkylenedioxy groups (e.g., C₁₋₃ alkylenedioxygroups such as methylenedioxy and ethylenedioxy), (iii) nitro groups,(iv) cyano groups, (v) optionally halogenated lower alkyl groups, (vi)optionally halogenated lower alkenyl groups, (vii) optionallyhalogenated lower alkynyl groups, (viii) lower cycloalkyl groups (e.g.,C₃₋₆ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl), (ix) lower alkoxy groups which may be substituted, (x)optionally halogenated lower alkylthio groups, (xi) hydroxy groups,(xii) amino groups, (xiii) mono-lower alkylamino groups (e.g., mono-C₁₋₆alkylamino groups such as methylamino, ethylamino, propylamino,isopropylamino and butylamino), (xiv) di-lower alkylamino groups (e.g.,di-C₁₋₆ alkylamino groups such as dimethylamino, diethylamino,dipropylamino and dibutylamino), (xv) 5- or 6-membered cyclic aminogroups (e.g., morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl),(xvi) lower alkyl-carbonyl groups (e.g., C₁₋₆ alkylcarbonyl groups suchas acetyl and propionyl), (xvii) carboxyl groups, (xviii) loweralkoxy-carbonyl groups (e.g., C₁₋₆ alkoxy-carbonyl groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl),(xix) carbamoyl groups or thiocarbamoyl groups, (xx) mono-loweralkyl-carbamoyl groups (e.g., mono-C₁₋₆ alkyl-carbamoyl groups such asmethylcarbamoyl and ethylcarbamoyl) or mono-lower alkyl-thiocarbamoylgroups (e.g., mono-C₁₋₆ alkyl-thiocarbamoyl groups such asmethylthiocarbamoyl and ethylthiocarbamoyl), (xxi) di-loweralkyl-carbamoyl groups (e.g., di-C₁₋₆ alkylcarbamoyl groups such asdimethylcarbamoyl and diethylcarbamoyl) or di-lower alkyl-thiocarbamoylgroups (e.g., di-C₁₋₆ alkylthiocarbamoyl groups such asdimethylthiocarbamoyl and diethylthiocarbamoyl), (xxii) aryl-carbamoyl(e.g., C₆₋₁₀ aryl-carbamoyl such as phenylcarbamoyl andnaphthylcarbamoyl) or aryl-thiocarbamoyl (e.g., C₆₋₁₀ aryl-thiocarbamoylsuch as phenylthiocarbamoyl and naphthylthiocarbamoyl), (xxiii) sulfogroups, (xxiv) lower alkylsulfonyl groups (e.g., C₁₋₆ alkylsulfonylgroups such as methylsulfonyl and ethylsulfonyl), (xxv) aryl groups(e.g., C₆₋₁₀ aryl groups such as phenyl and naphthyl), (xxvi) aryloxygroups (e.g., C₆₋₁₀ aryloxy groups such as phenyloxy and naphthyloxy),(xxvii) aralkyloxy groups (e.g., C₇₋₁₆ aralkyloxy groups such asbenzyloxy), and (xxviii) oxo groups.

Examples of the “optionally halogenated lower alkyl group” include loweralkyl groups (e.g., C₁₋₆ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine), specifically methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc.

Examples of the “optionally halogenated lower alkenyl group” and“optionally halogenated lower alkynyl group” include lower alkenylgroups (e.g., C₂₋₆ alkenyl groups such as vinyl, propenyl, isopropenyl,2-buten-1-yl, 4-penten-1-yl and 5-hexen-1-yl) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and loweralkynyl groups (e.g., C₂₋₆ alkynyl groups such as 2-butyn-1-yl,4-pentyn-1-yl and 5-hexyn-1-yl) optionally having 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine).

Examples of the “lower alkoxy groups which may be substituted” includelower alkoxy groups (e.g., C₁₋₆ alkoxy groups such as methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy)optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine), mono- or di-lower alkylamino groups (e.g., mono- ordi-C₁₋₆ alkylamino groups such as methylamino, dimethylamino, ethylaminoand dimethylamino) or lower alkoxy-carbonyl groups (e.g., C₁₋₆alkoxy-carbonyl groups such as methoxycarbonyl and ethoxycarbonyl).

Examples of the “optionally halogenated lower alkylthio group” includelower alkylthio groups (e.g., C₁₋₆ alkylthio groups such as methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio,sec-butylthio and tert-butylthio) optionally having 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine), specifically methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio andhexylthio.

Specific examples of the condensed ring formed by Ar¹ and Ar², alongwith the adjacent carbon atom, include condensed ring groups representedby the formula:

wherein R⁷ has the same definition as that shown above.

It is preferable that Ar¹ and Ar², whether identical or not, are anaromatic hydrocarbon group (e.g., C₆₋₁₄ aromatic hydrocarbon group)optionally having a substituent, and a benzene ring optionally having asubstituent is more preferred. More preferably, Ar¹ and Ar² areindependently (1) phenyl group which may be substituted by a halogenatom or C₁₋₆ alkyl, or (2) a 5- to 8-membered aromatic heterocyclicgroup containing 1 to 4 hetero atoms selected from among a nitrogenatom, a sulfur atom and an oxygen atom, in addition to carbon atoms.

In Formula (I) above, Ring B represents a “nitrogen-containingheterocycle optionally having a substituent,” provided that Ring B isnot a heterocycle represented by the formula:

wherein r is 0 or 1.

Examples of the “nitrogen-containing heterocycle” represented by Ring Binclude 3- to 13-membered nitrogen-containing heterocycles whichcontains one nitrogen atom, which may further contain 1 to 3 heteroatoms selected from among a nitrogen atom, an oxygen atom, a sulfuratom, etc. In Formula (I) above, it is preferable that Ring B form adivalent group resulting from removal of one hydrogen atom from thenitrogen atom and other atoms of Ring B, respectively. Specific examplesinclude 3- to 9-membered (more preferably 3- to 6-membered) nitrogenatom-containing heterocyclic groups such as

Examples of the substituent for the nitrogen-containing heterocyclerepresented by Ring B include the same as the substituent for the“aromatic group optionally having a substituent” represented by Ar¹ andAr² above.

Specific preferable examples of Ring B include a ring represented by theformula:

wherein Z is a nitrogen atom or a methine group, Z¹ and Z² areindependently a linear C₁₋₄ alkylene group which may be substituted by ahydroxy group, an oxo group or a C₁₋₆ alkyl group.

Examples of said “C₁₋₆ alkyl group” include linear or branched C₁₋₆alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl and hexyl.

Examples of said “linear C₁₋₄ alkylene group” include linear C₁₋₄alkylene groups such as methylene, ethylene, propylene and butylene.

Preferable examples of the “linear C₁₋₄ alkylene group which may besubstituted by a hydroxy group, an oxo group or a C₁₋₆ alkyl group”represented by Z¹ and Z² include unsubstituted linear C₁₋₄ alkylenegroups, and unsubstituted linear C₁₋₂ alkylene groups are morepreferred.

Ring B is more preferably piperidine, piperazine, or the like.

In Formula (I) above, X and Y, whether identical or not, are {circlearound (1)} a bond, {circle around (2)} an oxygen atom, {circle around(3)} S(O)p (p is an integer from 0 to 2), {circle around (4)} NR⁴wherein R⁴ is a hydrogen atom or a lower alkyl group, or {circle around(5)} a divalent linear lower hydrocarbon group which may contain asubstituent, and which may further contain 1 to 3 hetero atoms.

Examples of the lower alkyl group represented by R⁴ include linear orbranched C₁₋₆ alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Examples of the “divalent linear lower hydrocarbon group which mayfurther contain 1 to 3 hetero atoms” represented by X and Y includegroups resulting from removal of each of hydrogen atoms (2 in total)bound to the same or different carbon atom from a lower (C₁₋₆)hydrocarbon, and which may optionally contain hetero atoms selected fromamong an oxygen atom, a sulfur atom, etc., in the hydrocarbon chain.

Specific examples of the “divalent linear lower hydrocarbon group”include

(i) C₁₋₆ alkylene groups (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, etc.),

(ii) C₂₋₆ alkenylene groups (e.g., —CH═CH—, —CH═CH—CH₂—,—CH₂—CH═CH—CH₂—, —(CH₂)₂—CH═CH—CH₂—, —(CH₂)₂—CH═CH—(CH₂)₂—,—(CH₂)₃—CH═CH—CH₂—, etc.), and

(iii) C₂₋₆ alkynylene groups (e.g., —C≡C—, —C≡C—CH₂—, CH₂—C≡C—CH₂—,—(CH₂)₂—C≡C—CH₂—, —(CH₂)₂—C≡C—(CH₂)₂—, (CH₂)₃—C≡C—CH₂—, etc.).

Examples of the “substituent” for the “divalent linear lower hydrocarbongroup which may further contain 1 to 3 hetero atoms,” represented by Xand Y include the same as the “substituent” for the “aromatic groupoptionally having a substituent” represented by Ar¹ and Ar² above, andis preferably a hydroxy group or an oxo group.

X is preferably a bond, an oxygen atom or NH, and a bond or an oxygenatom is particularly preferred.

Preferable examples of Y include a group represented by the formula:

—(CH₂)m-Y¹—(CH₂)n-Y²—

wherein Y¹ and Y² whether identical or not, are a bond, an oxygen atom,S(O)p wherein p has the same definition as that shown above, NR⁴ whereinR⁴ has the same definition as that shown above, a carbonyl group, acarbonyloxy group or a group represented by the formula:

wherein R⁵ and R⁶, whether identical or not, are a hydroxy group or aC₁₋₄ alkyl group; m and n are independently an integer from 0 to 4 (sumof m and n is not more than 6).

Examples of the “C₁₋₄ alkyl group” represented by R⁵ and R⁶ includelinear or branched C₁₋₄ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Preferable examples of Y include

(i) C₁₋₆ alkylene groups, (ii) —(CH₂)p¹O—,

(iii) —(CH₂)p¹NH—,

(iv) —(CH₂)p¹S—,

(v) —(CH₂)q¹CH(OH)(CH₂)q²O—,

(vi) —(CH₂)q¹CH(OH)(CH₂)q²NH—,

(vii) —(CH₂)q¹CH(OH)(CH₂)q²S—,

(viii) —(CH₂)p¹CONH—,

(ix) —COO(CH₂)p¹O—,

(x) —COO(CH₂)p¹NH—,

(xi) —COO(CH₂)p¹S—,

(xii) —(CH₂)q¹O(CH₂)q²O—,

(xiii) —(CH₂)q¹O(CH₂)q²NH— or

(xiv) —(CH₂)q¹O(CH₂)q²S— wherein p¹ is an integer from 1 to 6, q¹ and q²are an integer from 1 to 3.

In particular, Y is preferably a bond, —(CH₂)₂—O—, —(CH₂)₃—O—,—(CH₂)₄—O—, —(CH₂)₆—O—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—,—(CH₂)₃—S—, —CH₂—CH(OH)—CH₂—O—, —(CH₂)₂—CO—NH—, —CH₂—CO—NH—,—CO—O—(CH₂)₂—O—, —CO—O—(CH₂)₃—O—, —(CH₂)₆—NH—, —(CH₂)₆—S—,—(CH₂)₂—O—(CH₂)₂—O—(CH₂)₂—O—(CH₂)₂—S—, or the like.

In the case of Compound (Ia), Y is preferably a group represented by theformula:

—(CH₂)m-Y³—(CH₂)n-Y⁴—

wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and mand n independently are an integer from 0 to 4 (sum of m and n is notmore than 6). In particular, m and n are preferably an integer from 1 to3, and 3 is more preferred. When Y³ is —CH(OH)—, m and n are preferably1.

In the case of Compound (Ib), Y is preferably a group represented by theformula:

—(CH₂)w-Y⁵—

wherein w is an integer from 1 to 6, and Y⁵ is an oxygen atom or NH. Inparticular, w is preferably an integer from 1 to 3, and 3 is morepreferred.

In Formula (I) above, R^(1a), whether identical or not, is a hydrogenatom, a halogen atom, a hydrocarbon group optionally having asubstituent, an acyl group or a hydroxy group having a substituent.

R^(1b), whether identical or not, is a hydrogen atom, a halogen atom, ahydrocarbon group optionally having a substituent, an acyl group or ahydroxy group having a substituent.

R² and R³, whether identical or not, are a hydrogen atom, a halogenatom, a hydrocarbon group optionally having a substituent, an acyl groupor a hydroxy group having a substituent.

Examples of the “halogen atom” represented by R^(1a), R^(1b), R² and R¹include a fluorine atom, a chlorine atom, a bromine atom and an iodineatom.

Examples of the “hydrocarbon group” of the “hydrocarbon group optionallyhaving a substituent” represented by R^(1a), R^(1b), R² and R³ includegroups resulting from removal of one hydrogen atom from a hydrocarboncompound, specifically linear or cyclic hydrocarbon groups such as alkylgroups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groupsand aralkyl groups. In particular, chain (linear or branched) or cyclichydrocarbon groups, etc. having 1 to 16 carbon atoms are preferred, withgreater preference given to

(a) alkyl groups, preferably lower alkyl groups (e.g., C₁₋₆ alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl and hexyl),

(b) alkenyl groups, preferably lower alkenyl groups (e.g., C₂₋₆ alkenylgroups such as vinyl, allyl, isopropenyl, butenyl, isobutenyl andsec-butenyl),

(c) alkynyl groups, preferably lower alkynyl groups (e.g., C₂₋₆ alkynylgroups such as propargyl, ethynyl, butynyl and 1-hexynyl),

(d) cycloalkyl groups, preferably lower cycloalkyl groups (e.g., C₃₋₆cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl which may condense with a benzene ring optionally having 1 to3 lower alkoxy groups (e.g., C₁₋₆ alkoxy groups such as methoxy),

(e) aryl groups (e.g., C₆₋₁₄ aryl groups such as phenyl, tolyl, xylyl,biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl,9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or9-phenanthryl, preferably phenyl groups), and

(f) aralkyl groups (preferably lower aralkyl groups (e.g., C₇₋₁₆ aralkylgroups such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl,2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentyl, morepreferably benzyl groups).

Examples of the “substituent” for said “hydrocarbon group” include thesame as the “substituent” for the “aromatic group optionally having asubstituent” represented by Ar¹ and Ar² above.

In particular, examples of preferred hydrocarbons include alkyl groupssuch as C₁₋₆ alkyl groups, and examples of substituents for hydrocarbongroups include cyano, carboxyl, C₁₋₆ alkoxy-carbonyl and carbamoyl (orthiocarbamoyl).

Examples of the “acyl group” represented by R^(1a), R^(1b), R² and R³include groups represented by the formula —(C═O)—R⁸, —SO₂—R⁸, —SO—R⁸,—(C═O)NR⁸R⁹, —(C═O)O—R⁸, —(C═S)O—R⁸ or —(C═S)NR⁸R⁹ wherein R⁸ is ahydrogen atom, a hydrocarbon group optionally having a substituent or ahydroxy group optionally having a substituent; and R⁹ is a hydrogen atomor a lower alkyl group (e.g., C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl orhexyl, preferably a C₁₋₃ alkyl group such as methyl, ethyl, propyl orisopropyl).

In particular, groups represented by the formula —(C═O)—R⁸, —SO₂—R⁸—,—SO—R⁸, —(C═O)NR⁸R⁹ or —(C═O)O—R⁸ are preferred, and groups representedby the formula —(C═O)—R⁸ are more preferred.

The “hydrocarbon group which may be substituted” represented by R⁸ isthe same as the “hydrocarbon group optionally having a substituent”represented by R^(1a), R^(1b), R² and R³ above. In particular, thehydrocarbon group represented by R⁸ is preferably an alkyl group such asa C₁₋₆ alkyl group, and the substituent thereof is preferably carboxyl,C₁₋₆ alkoxy-carbonyl, or the like. R⁹ is preferably a hydrogen atom orthe like.

Examples of the “hydroxy group optionally having a substituent”represented by R^(1a) include hydroxy groups having one group such as ahydrocarbon group optionally having a substituent, instead of a hydrogenatom of the hydroxy group.

Examples of the “hydroxy group optionally having a substituent”represented by R^(1b), R², R³ and R⁸ include (1) a hydroxy group or (2)a hydroxy group having one group such as a hydrocarbon group optionallyhaving a substituent, instead of a hydrogen atom of the hydroxy group.

The “hydrocarbon group optionally having a substituent” present in thehydroxy group is the same as the “hydrocarbon group optionally having asubstituent” represented by R^(1a), R^(1b), R², R³ and R⁸ above.

With respect to Compound (Ia), the acyl group represented by R^(1a),R^(1b), R² and R³ above is preferably {circle around (1)} a carboxylgroup, {circle around (2)} a C₁₋₆ alkoxy-carbonyl group, {circle around(3)} a carbamoyl group (or thiocarbamoyl group) which may be substitutedby a C₁₋₆ alkyl group optionally having carboxyl or C₁₋₆alkoxy-carbonyl, or the like.

In particular, R^(1a) is preferably (1) a hydrogen atom, (2) a carboxylgroup, (3) a C₁₋₆ alkoxy-carbonyl group, (4) a C₁₋₆ alkyl group whichmay be substituted by a group selected from the group consisting of (i)cyano, (ii) carboxyl, (iii) C₁₋₆ alkoxy-carbonyl and (iv) carbamoyl (orthiocarbamoyl) or (5) a carbamoyl group (or thiocarbamoyl group) whichmay be substituted by a C₁₋₆ alkyl group optionally having carboxyl orC₁₋₆ alkoxy-carbonyl, or the like.

With respect to Compound (Ib), when R^(1b) is a hydrogen atom, the oxogroup of the triazolo[4,3-b]pyridazine ring may be enolated, and thepartial structural formula:

may represent any of the formula:

In particular, R^(1b) is preferably

(1) a hydrogen atom,

(2) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii)C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆alkoxy-carbonyl, or the like.

With respect to Formula (I) above, R² and R³ are preferably a hydrogenatom.

In Formula (I) above, R⁷ represents a hydrogen atom, a hydroxy groupwhich may be substituted by a lower alkyl group or a carboxyl group.

Examples of the “lower alkyl group” of the “hydroxy group which may besubstituted by a lower alkyl group” include C₁₋₆ alkyl groups such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl and hexyl.

R⁷ is preferably a hydrogen atom or a hydroxy group, and a hydrogen atomis particularly preferred.

As Compound (I) of the present invention, the following are preferred:

COMPOUND (I)-I

Compound (I) wherein R^(1a) is

(1) a hydrogen atom,

(2) a carboxyl group,

(3) a C₁₋₆ alkoxy-carbonyl group,

(4) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆alkoxy-carbonyl and (iv) carbamoyl, or

(5) a carbamoyl group which may be substituted by a C₁₋₆ alkyl groupoptionally having carboxyl or C₁₋₆ alkoxy-carbonyl;

R^(1b) is

(1) a hydrogen atom, or

(2) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii)C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆alkoxy-carbonyl;

R² and R³ are a hydrogen atom;

R⁷ is a hydrogen atom or a hydroxy group (particularly a hydrogen atom);

Ar¹ and Ar² are independently a phenyl group which may be substituted;Ring B is a ring represented by the formula:

X is a bond or an oxygen atom;

Y is a group represented by the formula:

—(CH₂)m-Y³—(CH₂)n-Y⁴—

 wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and mand n are independently an integer from 0 to 6 (sum of m and n is notmore than 6).

COMPOUND (I)-II

{circle around (1)}6-[6-[4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazineor a salt thereof.

{circle around (2)}6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazineor a salt thereof.

{circle around (3)}3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino)propoxy][1,2,4]triazolo[4,3-b]pyridazineor a salt thereof.

{circle around (4)}6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylicacid or a salt thereof.

{circle around (5)}6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-oneor a salt thereof.

{circle around (6)} Ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateor a salt thereof.

{circle around (7)}2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionicacid or a salt thereof.

{circle around (8)} Pivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateor a salt thereof.

{circle around (9)} Pivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateor a salt thereof.

As Compound (Ia) of the present invention, the following are preferred:

COMPOUND (Ia)-I

Compound (Ia) wherein Ar¹ and Ar² are independently a phenyl group whichmay be substituted; Ring B is a ring represented by the formula:

X is a bond or an oxygen atom;

Y is a group represented by the formula:

—(CH₂)m-Y³—(CH₂)n-Y⁴—

 wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and mand n are independently an integer from 0 to 4 (sum of m and n is notmore than 6);

R^(1a) is

(1) a hydrogen atom,

(2) a carboxyl group,

(3) a C₁₋₆ alkoxy-carbonyl group,

(4) a C₁₋₆ alkyl group which may be substituted by a group selected fromthe group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆alkoxy-carbonyl and (iv) carbamoyl (or thiocarbamoyl), or

(5) a carbamoyl group (or thiocarbamoyl group) which may be substitutedby a C₁₋₆ alkyl group optionally having carboxyl or C₁₋₆alkoxy-carbonyl; and R², R³ and R⁷ are a hydrogen atom.

COMPOUND (Ia)-II

{circle around (1)}6-[6-(4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazineor a salt thereof.

{circle around (2)}6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazineor a salt thereof.

{circle around (3)}3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazineor a salt thereof.

{circle around (4)}6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylicacid or a salt thereof.

As Compound (Ib) of the present invention, the following are preferred:

COMPOUND (Ib)-I

Compound (Ib) wherein Ar¹ and Ar² are independently a phenyl group whichmay be substituted; Ring B is a ring represented by the formula:

X is an oxygen atom; Y is a group represented by the formula:

—(CH₂)w-Y⁵—

wherein w is an integer from 1 to 6, and Y⁵ is an oxygen atom or NH;R^(1b) is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group which may besubstituted by a group selected from the group consisting of (i)carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii) C₁₋₆ alkyl-carbonyloxy and(iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkoxy-carbonyl; and R², R³ and R⁷ area hydrogen atom.

COMPOUND (Ib)-II

{circle around (1)}6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-oneor a salt thereof.

{circle around (2)} Ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino)propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateor a salt thereof.

{circle around (3)}2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionicacid or a salt thereof.

{circle around (4)} Pivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateor a salt thereof.

{circle around (5)} Pivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)-2-methylpropionateor a salt thereof.

The pro-drug of Compound (I) of the present invention may be a compoundwhich is converted into Compound (I) by a reaction with an enzyme,gastric acid, or the like under physiological conditions in the livingbody, i.e., a compound which is converted into Compound (I) uponenzymatic oxidation, reduction, hydrolysis, or the like, or a compoundwhich is converted into Compound (I) upon hydrolysis or the like withgastric acid or the like.

Examples of the pro-drug of Compound (I) include compounds wherein theamino group of Compound (I) is acylated, alkylated, or phosphorylated(e.g., compounds wherein the amino group of Compound (I) iseicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,tert-butylated, or the like); compounds wherein the hydroxy group ofCompound (I) is acylated, alkylated, phosphorylated, or borated (e.g.,compounds wherein the hydroxy group of Compound (I) is acetylated,palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,alanylated, dimethylaminomethylcarbonylated, or the like); and compoundswherein the carboxyl group of Compound (I) is ethyl-esterified,phenyl-esterified, carboxymethyl-esterified,dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified,ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified,cyclohexyloxycarbonylethyl-esterified, methyl-amidated, or the like.These compounds can be produced by per se known methods from Compound(I).

In addition, the pro-drug of Compound (I) of the present invention maybe a compound which is converted into Compound (I) under physiologicalconditions as described in “Pharmaceutical Research and Development,”Vol. 7 (Drug Design), pages 163-198, published in 1990 by HirokawaPublishing Co. (Tokyo, Japan).

Methods for producing Compound (I) of the present invention or a saltthereof are described below.

(A) Of Compound (I) of the present invention or a salt thereof, Compound(Ia) or a salt thereof can be produced by reacting a compoundrepresented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the samedefinitions as those shown above, or a salt thereof, with a compoundrepresented by the formula:

wherein Q² represents a leaving group; the other symbols have the samedefinitions as those shown above, or a salt thereof.

Examples of the leaving group represented by Q¹ include alkali metalssuch as sodium and potassium. Q¹ may be a hydrogen atom.

Examples of the leaving group represented by Q² induce halogen atoms(e.g., chlorine atom, bromine atom, iodine atom), C₆₋₁₀ arylsulfonyloxygroups (e.g., benzenesulfonyloxy, p-tolylsulfonyloxy) and C₁₋₄alkyl-sulfonyloxy groups (e.g., methanesulfonyloxy).

In this reaction, Compound (IIa) or a salt thereof is normally used at 1to 5 mol, preferably 1 to 2 mol, per mol of Compound (IlIa) or a saltthereof. This condensation reaction is preferably carried out in thepresence of a base.

Examples of the base include alkali metal hydrides such as sodiumhydride and potassium hydride; alkali metal alkoxides such as sodiummethoxide and sodium ethoxide; alkali metal hydroxides such as sodiumhydroxide and potassium hydroxide; and alkali metal carbonates such assodium carbonate and potassium carbonate.

In addition, this reaction can also be carried out in an inert solventexemplified by alcohols such as methanol and ethanol; ethers such asdioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitriles such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

(B) Also, Compound (Ia) of the present invention or a salt thereof canbe produced by reacting a compound represented by the formula:

wherein the symbols have the same definitions as those shown above, or asalt thereof, with a compound represented by the formula:

wherein the symbols have the same definitions as those shown above, or asalt thereof.

In this reaction, Compound (IVa) or a salt thereof is normally used at 1to 5 mol, preferably 1 to 2 mol, per mol of Compound (Va) or a saltthereof. This condensation reaction is preferably carried out in thepresence of a base. Examples of the base include alkali metal hydridessuch as sodium hydride and potassium hydride; alkali metal alkoxidessuch as sodium methoxide and sodium ethoxide; alkali metal hydroxidessuch as sodium hydroxide and potassium hydroxide; and alkali metalcarbonates such as sodium carbonate and potassium carbonate.

In addition, this reaction can also be carried out in an inert solventexemplified by alcohols such as methanol and ethanol; ethers such asdioxane and tetrahydrbfuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitrites such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

(C) Compound (Ia) of the present invention or a salt thereof can beproduced by reacting a compound represented by the formula:

wherein the symbols have the same definitions as those shown above, or asalt thereof, with a compound represented by the formula:

wherein the symbols have the same definitions as those shown above, or asalt thereof.

In this reaction, Compound (VIa) or a salt thereof is normally used at 1to 5 mol, preferably 1 to 2 mol, per mol of Compound (VIIa) or a saltthereof.

In addition, this reaction can also be carried out in an inert solventexemplified by alcohols such as methanol and ethanol; ethers such asdioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitrites such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

(D) Also, Compound (Ia) of the present invention or a salt thereof canbe produced by reacting a compound represented by the formula:

wherein R^(1a′) is a cyano group, an alkoxycarbonyl group, a carboxylgroup, a substituted carbamoyl group, or a C₁₋₆ alkyl group which may besubstituted by cyano, alkoxycarbonyl, carboxyl, substituted carbamoyl,or the like; the other symbols have the same definitions as those shownabove, or a salt thereof, with an acid or a base.

Examples of the alkoxycarbonyl group represented by R^(1a) include C₁₋₆alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, and butoxycarbonyl.

Examples of the substituted carbamoyl group represented by R^(1a′)include mono-lower alkyl-carbamoyl groups (e.g., mono-C₁₋₆alkyl-carbamoyl groups such as methylcarbamoyl and ethylcarbamoyl),di-lower alkyl-carbamoyl groups (e.g., di-C₁₋₆ alkylcarbamoyl groupssuch as dimethylcarbamoyl and diethylcarbamoyl), and aryl-carbamoylgroups (e.g., C₆₋₁₀ aryl-carbamoyl groups such as phenylcarbamoyl andnaphthylcarbamoyl).

Examples of the C₁₋₆ alkyl group represented by R^(1a′) include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, and hexyl. The alkoxycarbonyl and substituted carbamoyl which isa substituent for this C₁₋₆ alkyl group is the same as thealkoxycarbonyl and substituted carbamoyl represented by R^(1a′).

In this reaction, an acid or a base is normally used at 1 to 5 mol,preferably 1 to 2 mol, per mol of Compound (Ia′) or a salt thereof.

Examples of the base used for this reaction include alkali metalhydrides such as sodium hydride and potassium hydride; alkali metalalkoxides such as sodium methoxide and sodium ethoxide; alkali metalhydroxides such as sodium hydroxide and potassium hydroxide; and alkalimetal carbonates such as sodium carbonate and potassium carbonate.

Examples of the acid used for this reaction include inorganic acids suchas hydrochloric acid, sulfuric acid and nitric acid.

In addition, this reaction can also be carried out in a solventexemplified by water; alcohols such as methanol and ethanol; ethers suchas dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitriles such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

Compound (Ia) thus obtained can be converted into a salt by aconventional method. When Compound (Ia) is obtained as a salt, it can beconverted into a free form or another salt by a conventional method.Compound (Ia) or a salt thereof thus obtained can be isolated andpurified by known means such as solvent extraction, liquid-liquidtransformation, re-dissolution, salting-out, crystallization,recrystallization and chromatography. When Compound (Ia) or a saltthereof contains optical isomers, it can be resolved into the R- andS-configurations by an ordinary means of optical resolution.

Methods for producing Starting Compounds (IIa) through (VIIIa) or saltsthereof which are used to produce Compound (Ia) of the present inventionor a salt thereof are described below.

Salts of these Compounds (Ia) through (VIIIa) include, for example,salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid,hydrobromic acid, sulfuric acid) and salts with organic acids (e.g.,acetic acid, formic acid, propionic acid,fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,methanesulfonic acid, benzenesulfonic acid). Provided that thesecompounds have an acidic group such as that of a carboxylic acid, as asubstituent, the acidic group may form a salt with an inorganic base(e.g., alkali metal or alkaline earth metal such as sodium, potassium,calcium or magnesium, or ammonia) or an organic base (e.g., tri-C₁₋₃alkylamine such as triethylamine).

Starting Compounds (IIa) and (IVa) or salts thereof can, for example, besynthesized by the method described in the Journal of MedicinalChemistry, Vol. 32, p. 583 (1989), or a modification thereof.

Starting Compound (IIIa) or a salt thereof can, for example, besynthesized by the method described in the Journal of the PharmaceuticalSociety of Japan, Vol. 75, p. 1242 (1955), or a modification thereof.

Starting Compounds (Va) and (VIIa) or salts thereof can, for example, besynthesized by the methods described in Japanese Patent UnexaminedPublication No. 223287/1991 etc., or modifications thereof.

Starting Compounds (VIa) or a salt thereof can, for example, besynthesized by the method described in the Journal of MedicinalChemistry, Vol. 38, p. 2472 (1995), or a modification thereof.

Although these starting compound or salts thereof thus obtained can beisolated and purified by known means such as solvent extraction,liquid-liquid transformation, re-dissolution, salting-out,crystallization, recrystallization and chromatography, they may also beused as a starting material for the next process in the form of areaction mixture as-is without isolation.

(A) On the other hand, Compound (Ib) of the present invention or a saltthereof can be produced by reacting a compound represented by theformula:

wherein the symbols have the same definitions as those shown above, or asalt thereof, with a compound represented by the formula:

wherein the symbols have the same definitions as those shown above, or asalt thereof.

In this reaction, Compound (IIb) or a salt thereof is normally used at 1to 5 mol, preferably 1 to 2 mol, per mol of Compound (IIIb) or a saltthereof. This condensation reaction is preferably carried out in thepresence of a base. Examples of the base include alkali metal hydridessuch as sodium hydride and potassium hydride; alkali metal alkoxidessuch as sodium methoxide and sodium ethoxide.; alkali metal hydroxidessuch as sodium hydroxide and potassium hydroxide; and alkali metalcarbonates such as sodium carbonate and potassium carbonate.

In addition, this reaction can also be carried out in a solventexemplified by alcohols such as methanol and ethanol; ethers such asdioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitrites such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

(B) Also, Compound (Ib) of the present invention or a salt thereof canbe produced by reacting a compound represented by the formula:

wherein the symbols have the same definitions as those shown above, or asalt thereof, with a compound represented by the formula:

Q²—R^(1b)  (Vb)

wherein the symbols have the same definitions as those shown above, or asalt thereof.

In this reaction, Compound (Vb) or a salt, thereof is normally used at 1to 5 mol, preferably 1 to 2 mol, per mol of Compound (IVb) or a saltthereof. This condensation reaction is preferably carried out in thepresence of a base. Examples of the base include alkali metal hydridessuch as sodium hydride and potassium hydride; alkali metal alkoxidessuch as sodium methoxide and sodium ethoxide; alkali metal hydroxidessuch as sodium hydroxide and potassium hydroxide; and alkali metalcarbonates such as sodium carbonate and potassium carbonate.

In addition, this reaction can also be carried out in an inert solventexemplified by alcohols such as methanol and ethanol; ethers such asdioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitrites such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

(C) Also, Compound (Ib) of the present invention or a salt thereof canbe produced by reacting a compound represented by the formula:

wherein R^(1b′) is a cyano group, an alkoxycarbonyl group, a carboxylgroup, a substituted carbambyl group, or a C₁₋₆ alkyl group which may besubstituted by cyano, alkoxycarbonyl, carboxyl, substituted carbamoyl,or the like; the other symbols have the same definitions as those shownabove, or a salt thereof, with an acid or a base. Each group representedby R^(1b′) has the same definition as that represented by R^(1a′).

In this reaction, an acid or a base is normally used at 1 to 5 mol,preferably 1 to 2 mol, per mol of Compound (Ib′) or a salt thereof.

Examples of the base used for this reaction include alkali metalhydrides such as sodium hydride and potassium hydride; alkali metalalkoxides such as sodium methoxide and sodium ethoxide; alkali metalhydroxides such as sodium hydroxide and potassium hydroxide; and alkalimetal carbonates such as sodium carbonate and potassium carbonate.

Examples of the acid used for this reaction include inorganic acids suchas hydrochloric acid, sulfuric acid and nitric acid.

In addition, this reaction can also be carried out in an inert solventexemplified by water; alcohols such as methanol and ethanol; ethers suchas dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene,toluene and xylene; nitrites such as acetonitrile; amides such asN,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such asdimethyl sulfoxide.

Reaction temperature is normally 10 to 200° C., preferably 50 to 100° C.

Reaction time is normally 30 minutes to 24 hours, preferably 1 to 6hours.

Compound (Ib) thus obtained can be converted into a salt by aconventional method. When Compound (Ib) is obtained as a salt, it can beconverted into a free form or another salt by a conventional method.Compound (Ib) or a salt thereof thus obtained can be isolated andpurified by known means such as solvent extraction, liquid-liquidtransformation, re-dissolution, salting-out, crystallization,recrystallization and chromatography. When Compound (Ib) or a saltthereof contains optical isomers, they can be resolved into the R- andS-configurations by an ordinary means of optical resolution.

Methods for producing Starting Compounds (IIb) and (IIIb) or saltsthereof which are used to produce Compound (Ib) of the present inventionor a salt thereof are described below.

Salts of these Compounds (Ib) through (IIIb) include, for example, saltswith inorganic acids (e.g., hydrochloric acid, phosphoric acid,hydrobromic acid, sulfuric acid) and salts with organic acids (e.g.,acetic acid, formic acid, propionic acid, fumaric acid, maleic acid,succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,methanesulfonic acid, benzenesulfonic acid). Provided that thesecompounds have an acidic group such as that of a carboxylic acid, as asubstituent, the acidic group may form a salt with an inorganic base(e.g., alkali metal or alkaline earth metal such as sodium, potassium,calcium or magnesium, or ammonia) or an organic base (e.g., tri-C₁₋₃alkylamine such as triethylamine).

Starting Compound (IIb) or a salt thereof can, for example, besynthesized by the method described in the Journal of MedicinalChemistry, Vol. 32, p. 583 (1989), or a modification thereof.

Starting Compound (IIIb) or a salt thereof can, for example, besynthesized by the method described in the Journal of HeterocyclicChemistry, Vol. 13, p. 673 (1976), or a modification thereof.

Although these starting compound or salts thereof thus obtained can beisolated and purified by known means such as solvent extraction,liquid-liquid transformation, re-dissolution, salting-out,crystallization, recrystallization and chromatography, they may also beused as a starting material for the next process in the form of areaction mixture as-is without isolation.

Also, when the starting compound used in each of the above-mentionedreactions for producing Compounds (Ia) and (Ib) of the present inventionor salts thereof or for synthesizing starting compounds has an aminogroup, a carboxyl group or a hydroxyl group as a substituent, thesesubstituents may have a protective group in common use in peptidechemistry etc. incorporated therein; the desired compound can beobtained by removing, as appropriate, the protective group aftercompletion of the reaction.

Amino group-protecting groups include, for example, formyl, C₁₋₆alkylcarbonyls optionally having a substituent (e.g., acetyl,ethylcarbonyl), phenylcarbonyl, C₁₋₆ alkyl-oxycarbonyls (e.g.,methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl, C₇₋₁₀aralkyl-carbonyls (e.g., benzylcarbonyl), trityl, phthaloyl andN,N-dimethylaminomethylene. Substituents for these groups includehalogen atoms (e.g., fluorine, chlorine, bromine, iodine), C₁₋₆alkyl-carbonyls (e.g., mrethylcarbonyl, ethylcarbonyl, butylcarbonyl)and nitro groups, the number of substituents being about 1 to 3.

Carboxyl group-protecting groups include, for example, C₁₋₆ alkylsoptionally having a substituent (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, tert-butyl), phenyl, trityl and silyl. Substituentsfor these groups include halogen atoms (e.g., fluorine, chlorine,bromine, iodine), formyl, C₁₋₆ alkyl-carbonyls (e.g., acetyl,ethylcarbonyl, butylcarbonyl) and nitro groups, the number ofsubstituents being about 1 to 3.

Hydroxy group-protecting groups include, for example, C₁₋₆ alkylsoptionally having a substituent (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, tert-butyl), phenyl, C₇₋₁₀ aralkyls (e.g., benzyl),formyl, C₁₋₆ alkyl-carbonyls (e.g., acetyl, ethylcarbonyl),phenyloxycarbonyl, benzoyl, C₇₋₁₀ aralkyl-carbonyls (e.g.,benzylcarbonyl), pyranyl, furanyl and silyl. Substituents for thesegroups include halogen atoms (e.g., fluorine, chlorine, bromine,iodine), C₁₋₆ alkyls (e.g., methyl, ethyl, n-propyl), phenyl, C₇₋₁₀aralkyls (e.g., benzyl) and nitro groups, the number of substituentsbeing about 1 to 4.

The protecting groups can be removed by commonly known methods ormodifications thereof, including treatments with acids, bases, reducingagents, ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate,etc.

The compound (I) of the present invention or a salt thereof (including apro-drug of the compound (I)) can be safely used as an anti-allergicagent in mammals (e.g., humans, mice, dogs, rats, bovines), because itexhibits excellent anti-allergic, anti-histaminic, anti-inflammatory,anti-PAF (platelet-activating factor) or eosinophilchemotaxis-inhibiting activity, etc., with low toxicity (acute toxicity:LD₅₀>2 g/kg).

Furthermore, the compound (I) of the present invention or a salt thereofexhibits an eosinophil chemotaxis-inhibiting activity as well as ananti-histaminic activity, and can be used to treat or prevent allergicdiseases such as chronic urticaria and other forms of urticaria (e.g.,acute urticaria), atopic dermatitis, allergic rhinitis, allergicconjunctivitis, and hypersensitivity pneumonitis; dermal diseases(especially allergic dermal diseases) such as itching, herpeticdermatitis, eczematous dermatitis, contact dermatitis, prurigo, andpsoriasis; respiratory diseases such as eosinophilic pneumonia (PIEsyndrome), chronic obstructive pulmonary disease (COPD), and asthma;increased nasal cavity resistance, sneezing, nasal discharge,pollenosis, upper airway hypersensitivity, etc., in the mammalsmentioned above. In particular, Compound (I) or a salt thereof is usedas a preventive or therapeutic agent for asthma, allergicconjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis,or the like. The route of administration may be oral or non-oral.

Also, the preparation for the present invention may contain as activeingredients pharmaceutical components other than the compound (I) or asalt therof. Such pharmaceutically active components include, forexample, anti-asthmatics (e.g., theiphylline, procaterol, ketotifen,azelastine, seratrodast), anti-allergic agents (g.g., ketotifen,terfenadine, azelastine, epinastine), anti-inflammatory agents (e.g.,cefixime, cefdinir, ofloxacin, tosufloxacin) and antifungal agents(e.g., fluconazole, itraconazole). These components are not subject tolimitation, as long as the object of the present invention isaccomplished, and may be used in appropriate mixing ratios. Usefuldosage forms include, for example, tablets (including sugar-coatedtablets and film-coated tablets), pills, capsules (includingmicrocapsules), granules, fine granules, powders, syrups, emulsions,suspensions, injectable preparations, inhalants, ointments, eyedrops,aerosols, eye ointments, plasters, suppositories, troches, poultices,and liniments, these preparations are prepared by conventional methods(e.g., methods described in the Japanese Pharmacopoeia).

In the preparation of the present invention, the content of the compound(I) or a salt thereof is normally about 0.01 to 100% by weight,preferably 0.1 to 50% by weight, and more preferably 0.5 to 20% byweight, relative to the entire preparation, depending on the form of thepreparation.

Specifically, tablets can be produced by granulating a pharmaceuticalas-is, or in a uniform mixture with an excipient, a binder, adisintegrating agent or other appropriate additives, by an appropriatemethod, then adding lubricants etc., and subjecting the mixture tocompressive shaping, or by subjecting to direct compressive shaping apharmaceutical as-is, or in a uniform mixture with an excipient, abinder, a disintegrating agent or other appropriate additives, orsubjecting to compressive shaping previously prepared granules as-is, orin a uniform mixture with appropriate additives. These tablets mayincorporate coloring agents, correctives etc. as necessary, and may becoated with appropriate coating agents.

Injectable preparations can be produced by dissolving, suspending oremulsifying a given amount of a pharmaceutical in an aqueous solventsuch as water for injection, physiological saline or Ringer's solution,or a non-aqueous solvent such as a vegetable oil, and diluting to agiven amount, or transferring a given amount of a pharmaceutical into acontainer for injection and sealing the container.

Examples of the carriers for oral preparations include substances incommon use in pharmaceutical production, such as starch, mannitol,crystalline cellulose and carboxymethyl cellulose sodium. Examples ofthe carriers for injectable preparations include distilled water,physiological saline, glucose solutions and transfusions. Otheradditives in common use for pharmaceutical production can also be added,as appropriate.

Depending on patient age, body weight, symptoms, route and frequency ofadministration and other factors, the daily dose of these preparationsis normally 0.1 to 100 mg/kg, preferably 1 to 50 mg/kg, and morepreferably 1 to 10 mg/kg, based on daily dose of active ingredient(Compound (I) or a salt thereof), once or in two portions daily for eachasthmatic adult.

The present invention is hereinafter described in more detail by meansof the following reference examples, working examples (Examples),formulation examples and experimental examples, which are not to beconstrued as limitative.

In the working examples and reference examples below, the fractioncontaining the desired product was detected by observation via TLC(thin-layer chromatography).

In the TLC observation, 60F254, produced by Merck, was used as a TLCplate, with a UV detector as a means of detection.

The silica gel used for column chromatography was Merck Silica Gel 60(70-230 mesh).

The abbreviations used herein have the definitions shown below.

J: Coupling constant

s: Singlet

t: Triplet

m: Multiplet

Hz: Hertz

d: Doublet

q: Quartet

¹H-NMR: Proton nuclear magnetic resonance

CDCl₃: Deuterated chloroform

v/v: Volume/volume

%: % by weight

COMPOUND (Ia): REFERENCE EXAMPLE 1a Production of3-tert-Butyl-6-chloro[1,2,4]triazolo[4,3-b]pyridazine

2.78 g of N′-(6-chloro-3-pyridazinyl)-2,2-dimethylpropionohydrazide wasstirred under heating at an external temperature of 170° C. for 10minutes. After cooling, the reaction mixture was dissolved in ethylacetate, subjected to silica gel column chromatography, and eluted withethyl acetate. The desired fraction was collected and concentrated underreduced pressure; the precipitated crystal was washed with hexane anddried to yield 2.38 g of the title compound.

Melting point: 150-152° C.; Elemental analysis (for C₉H₁₁N₄Cl):Calculated (%): C, 51.31; H, 5.26; N, 26.60; Found (%): C, 51.36; H,5.17; N, 26.62.

REFERENCE EXAMPLE 2a Production of6-(2-Oxiranylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine

12.0 g of 2-oxiranylmethanol and 2.50 g of6-chloro[1,2,4]triazolo[4,3-b]pyridazine were dissolved in 40 ml ofN,N-dimethylformamide; under ice cooling, 713 mg of 60% oily sodiumhydride was added, followed by stirring at room temperature for 30minutes. After cold saline was added, the reaction mixture was extractedwith ethyl acetate-tetrahydrofuran (1:1) and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol (10:1). The desired fraction was collected andconcentrated under reduced pressure; the precipitated crystal was washedwith diethyl ether and dried to yield 1.02 g of the title compound.

¹H-NMR (CDCl₃) δ ppm: 2.78 (1H, dd, J=2.5, 4.7 Hz), 2.96 (1H, t, J=4.4Hz), 3.47-3.89 (1H, m), 4.20 (1H, dd, J=6.6, 12.0 Hz), 4.70 (1H, dd,J=2.9, 12.1 Hz), 6.87 (1H, d, J=10.0 Hz), 8.01 (1H, d, J=9.8 Hz), 8.86(1H, s).

REFERENCE EXAMPLE 3a Production of2-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-2-methylpropionitrile

Process A: Production ofN′-(6-Chloro-3-pyridazinyl)-2-cyano-2-methylpropionohydrazide

4.15 g of 2-cyano-2-methylpropionic acid was dissolved in 40 ml oftetrahydrofuran; under ice cooling, 5.95 g of N,N′-carbonyldiimidazolewas added. After stirring at room temperature for 50 minutes, 5.05 g of(6-chloro-3-pyridazinyl)hydrazine was added under ice cooling, followedby stirring at room temperature for 40 minutes. After saline was added,the reaction mixture was-extracted with ethyl acetate-tetrahydrofuran(1:1) and dried over magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate. The desired fraction wascollected and concentrated under reduced pressure; the precipitatedcrystal was washed with diethyl ether and dried to yield 7.04 g of thetitle compound.

¹H-NMR (CDCl₃) δ ppm: 1.62 (6H, s), 7.00 (1H, d, J=9.4 Hz), 7.51 (1H, d,J=9.2 Hz), 9.22 (1H, s), 10.4 (1H, s).

Process B:

6.43 g of N′-(6-chloro-3-pyridazinyl)-2-cyano-2-methylpropionohydrazidewas stirred under heating at an external temperature of 160° C. for 20minutes. After cooling, water was added; the reaction mixture wasextracted with ethyl acetate-tetrahydrofuran (1:1), washed withsaturated saline, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate. The desired fraction wascollected and concentrated under reduced pressure; the precipitatedcrystal was washed with diethyl ether and dried to yield 3.65 g of thetitle compound.

Melting point: 153-155° C.; Elemental analysis (for C₉H₈N₅Cl):Calculated (%): C, 48.77; H, 3.64; N, 31.60; Found (%): C, 48.69; H,3.69; N, 31.55.

REFERENCE EXAMPLE 4a Production of Ethyl6-Chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate

7.04 g of (6-chloro-3-pyridazinyl)hydrazine was dissolved in 70 ml ofethanol; 8.6 ml of diethyl oxalate was added, followed by stirring atroom temperature for 16 hours and subsequent refluxing under heating for1 day. After cooling, the precipitated crystal was washed with diethylether and dried to yield 7.32 g of the title compound.

¹H-NMR (CDCl₃) δ ppm: 1.52 (3H, t, J=7.0 Hz), 4.61 (2H, q, J=7.0 Hz),7.33 (1H, d, J=9.6 Hz), 8.24 (1H, d, J=10.0 Hz).

REFERENCE EXAMPLE 5a Production ofN-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycineEthyl Ester

329 mg of (6-chloro-3-pyridazinyl)hydrazine was dissolved in 3 ml ofethanol; 206 mg of N-(ethyloxalyl)-2,2-dimethylglycine ethyl ester wasadded. After stirring at room temperature for 15 hours, the reactionmixture was refluxed under heating for 16 hours; the ethanol wasdistilled off, followed by stirring under heating at an externaltemperature of 110° C. for 5 hours. After cooling, saline was added; thereaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1)and dried over sodium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate. The desired fraction was collected andconcentrated under reduced pressure; the precipitated crystal was washedwith diethyl ether-hexane (1:1) and dried to yield 154 mg of the titlecompound.

Melting point: 132-133° C.; Elemental analysis (for C₁₂H₁₄N₅O₃Cl):Calculated (%): C, 46.24; H, 4.53; N, 22.47; Found (%): C, 46.27; H,4.58; N, 22.54.

REFERENCE EXAMPLE 6a Production ofN-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)glycine EthylEster

4.05 g of (6-chloro-3-pyridazinyl)hydrazine was dissolved in 20 ml ofethanol; 5.69 g of N-(ethyloxalyl)glycine ethyl ester was added; whilethe ethanol was evaporated, the reaction mixture was refluxed underheating for 2 days. After cooling, water was added; the reaction mixturewas extracted with ethyl acetate-tetrahydrofuran (1:1), washed withsaturated saline, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate. The desired fraction wascollected and concentrated under reduced pressure; the precipitatedcrystal was washed with diethyl ether and dried to yield 1.99 g of thetitle compound.

Melting point: 133-134° C.; Elemental analysis (for C₁₀H₁₀N₅O₃Cl):Calculated (%): C, 42.34; H, 3.55; N, 24.69; Found (%): C, 42.47; H,3.44; N, 24.88.

EXAMPLE 1a Production of6-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy][1,2,4]triazolo[4,3-b]pyridazine

0.311 g of 4-(diphenylmethyl)-1-piperazinepropanol was dissolved in 5 mlof N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added;the reaction mixture was stirred in an oil bath (60° C.) for 30 minutes.After cooling, 0.232 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine wasadded; the reaction mixture was stirred in an oil bath. (bathtemperature 60° C.) for 40 minutes. After cooling, ice water was added;the reaction mixture was extracted with ethyl acetate; the extract waswashed with saline and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(90:10:1). The desired fraction was collected and concentrated; thecrystal obtained was filtered, washed with ethyl ether, and dried, toyield 0.339 g of the title compound.

Melting point: 132-134° C.; Elemental analysis (for C₂₅H₂₈N₆O):Calculated (%): C, 70.07; H, 6.59; N, 19.61; Found (%): C, 69.71; H,6.55; N, 19.48.

EXAMPLE 2a Production of6-[3-[4-(Diphenylmethyl)-1-piperazinyl]propylthio][1,2,4]triazolo[4,3-b]pyridazine

Process A: 6-(3-Chloropropylthio)[1,2,4]triazolo[4,3-b]pyridazine

7.8 ml of methyl 3-mercaptopropionate was dissolved in 80 ml ofmethanol; 30 ml of a 2 N solution of sodium methoxide in methanol and3.10 g of 6-chloro[1,2,4]triazolo[4,3 b]pyridazine were added, followedby refluxing under heating for 40 minutes. After cooling, the reactionmixture was concentrated under reduced pressure; to the residue, ethylacetate was added; the precipitated crystal was collected, washed withethyl acetate, and suspended in 80 ml of tetrahydrofuran; 3.95 ml of1-bromo-3-chloropropane was added; followed by refluxing under heatingfor 2.5 hours. After cooling, ice water was added; the reaction mixturewas extracted with ethyl acetate; the extract was washed with saline anddried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate. The desired fraction was collected andconcentrated; the crystal obtained was collected to yield 3.95 g of thetitle compound.

Melting point: 79-80° C.; Elemental analysis (for C₈H₉N₄SCl): Calculated(%): C, 42.01; H, 3.97; N, 24.50; Found (%): C, 41.92; H, 3.72; N,24.64.

Process B:

0.458 g of 6-(3-chloropropylthio)[1,2,4]triazolo[4,3-b]pyridazine and0.505 g of 1-(diphenylmethyl)piperazine were dissolved in 15 ml ofacetonitrile; 0.447 g of sodium iodide and 0.277 g of potassiumcarbonate were added, followed by refluxing under heating for 6 hours.After cooling, ice water was added; the reaction mixture was extractedwith ethyl acetate; the extract was washed with saturated saline anddried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol (90:10). The desired fraction wascollected and concentrated; the crystal obtained was recrystallized fromethyl acetate to yield 0.335 g of the title compound.

Melting point: 143-144° C.; Elemental analysis (for C₂₅H₂₈N₆S):Calculated (%): C, 67.54; H, 6.35; N, 18.90; Found (%): C, 67.34; H,6.40; N, 18.91.

EXAMPLE 3a Production of6-[3-[4-(Diphenylmethoxy)piperidino]propylthio][1,2,4]triazolo[4,3-b]pyridazineFumarate (2:3)

0.458 g of 6-(3-chloropropylthio)[1,2,4]triazolo[4,3-b]pyridazine and0.534 g of 4-(diphenylmethoxy)piperidine were dissolved in 15 ml ofacetonitrile; 0.447 g of sodium iodide and 0.277 g of potassiumcarbonate were added, followed by refluxing under heating for 15 hours.After cooling, ice water was added; the reaction mixture was extractedwith ethyl acetate; the extract was washed with saturated saline anddried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol-triethylamine (90:10:1). Thedesired fraction was collected and concentrated; the residue wasdissolved in 20 ml of ethanol; 0.185 g of fumaric acid was added. Theprecipitated crystal was collected, washed with ethanol, and dried, toyield 0.396 g of the title compound.

Melting point: 148-150° C.; Elemental analysis (forC₂₆H₂₉N₅OS.1.5(C₄H₄O₄)): Calculated (%): C, 60.65; H, 5.57; N, 11.05;Found (%): C, 60.72; H, 5.44; N, 11.19.

EXAMPLE 4a Production of6-[3-(4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine

0.464 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine and 1.26 g of4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of1-butanol; 0.62 ml of N-ethyldiisopropylamine was added, followed byrefluxing under heating for 12 hours. After ice water and sodiumhydrogen carbonate were added, the reaction mixture was extracted withethyl acetate; the extract was washed with saturated saline and driedover magnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol-triethylamine (90:10:1). The desiredfraction was collected and concentrated; the crystal obtained was washedwith ethyl acetate and dried to yield 0.648 g of the title compound.

Melting point: 167-168° C.; Elemental analysis (for C₂₆H₃₀N₆O):Calculated (%): C, 70.56; H, 6.83; N, 18.99; Found (%): C, 70.21; H,6.75; N, 19.06.

EXAMPLE 5a Production of6-[4-[4-(Diphenylmethoxy)piperidino]butylamino][1,2,4]triazolo[4,3-b]pyridazine

1.15 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 578 mg of6-chloro[1,2,4]triazolo[4,3-b]pyridazine were dissolved in 20 ml of1-butanol; 1.17 ml of N-ethyldiisopropylamine was added, followed byrefluxing under heating for 14 hours. After cooling, ethyl acetate wasadded; the reaction mixture was washed with aqueous sodium bicarbonateand saturated saline and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; the residue wascrystallized from ethyl acetate and dried to yield 611 mg of the titlecompound.

Melting point: 145-146° C.; Elemental analysis, (for C₂₇H₃₂N₆O):Calculated (%): C, 71.03; H, 7.06; N, 18.41; Found (%): C, 70.95; H,7.02; N, 18.73.

EXAMPLE 6a Production of6-(2-[4-(Diphenylmethoxy)piperidino]ethoxy][1,2,4]triazolo[4,3-b]pyridazine

610 mg of 4-(diphenylmethoxy)-1-piperidine ethanol was dissolved in 15ml of tetrahydrofuran; 207 mg of sodium tert-butoxide was added; thereaction mixture was stirred at an external temperature of 60° C. for 40minutes. After cooling, 303 mg of6-chloro,1,2,4]triazolo[4,3-b]pyridazine was added, followed byrefluxing under heating for 8 hours. After cooling, water was added, andthe mixture was extracted with ethyl acetate, washed with saturatedsaline, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(50:5:1). The desired fraction was collected and concentrated underreduced pressure; the residue was crystallized from small amounts ofethyl acetate and diethyl ether, washed with diethyl ether, and dried,to yield 449 mg of the title compound.

Melting point: 149-150° C.; Elemental analysis (for C₂₅H₂₇N₅O₂):Calculated (%): C, 69.91; H, 6.34; N, 16.31; Found (%): C, 69.91; H,6.08; N, 16.31.

EXAMPLE 7a Production of6-[6-[4-(Diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazineFumarate

825 mg of 4-(diphenylmethoxy)-1-piperidinehexanol was dissolved in 13 mlof tetrahydrofuran; 108 mg of sodium hydride (60% in oil) was added,followed by refluxing under heating for 1.5 hours. After cooling, 347 mgof 6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added, followed byrefluxing under heating for 2 hours. After cooling, water was added; thereaction mixture was extracted with ethyl acetate, washed with saturatedsaline, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(50:5:1). The desired fraction was collected and concentrated underreduced pressure; 940 mg of the residue was dissolved in ethanol; asolution of 225 mg of fumaric acid in ethanol was added, followed byconcentration under reduced pressure. The residue was crystallized fromethanol-ethyl acetate (1:5), washed with ethyl acetate, and dried, toyield 939 mg of the title compound.

¹H-NMR (CDCl₃) δ ppm: 1.30-1.55 (4H, m), 1.65-1.85 (4H, m), 1.85-2.20(4H, m), 2.80-3.35 (5H, m), 3.73 (1H, brs), 4.27 (2H, t, J 6.4 Hz), 5.44(1H,s), 6.76(2H, S), 6.78 (1H, d, J=9.6 Hz), 7.25-7.35 (10H, m), 7.94(1H, d, J=9.8 Hz), 8.87 (1H, s). Melting point: 144-146° C.; Elementalanalysis (for C₃₃H₃₉N₅O₆): Calculated (%): C, 65.87; H, 6.53; N, 11.64;Found (%): C, 65.81; H, 6.48; N, 10.87.

EXAMPLE 8a Production of6-[6-[4-(Diphenylmethyl)-1-piperazinyl]hexyloxy][1,2,4]triazolo[4,3-b]pyridazinefumarate

529 mg of 4-(diphenylmethyl)-1-piperazinehexanol was dissolved in 8 mlof tetrahydrofuran; 90 mg of sodium hydride (60% in oil) was added,followed by stirring for 1 hour. After cooling, 232 mg of6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added, followed byrefluxing under heating for 2 hours. After cooling, water was added; thereaction mixture was extracted with ethyl acetate, washed with saturatedsaline, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol (10:1). Thedesired fraction was collected and concentrated under reduced pressure;320 mg of the residue was dissolved in ethanol; a solution of 71 mg offumaric acid in ethanol was added, followed by concentration underreduced pressure residue was crystallized from ethanol-ethylacetate-diethyl ether (1:2:2), washed with diethyl ether, and dried, toyield 113 mg of the title compound.

Melting point: 162-163° C.; Elemental analysis (for C₃₂H₃₈N₆O₅):Calculated (%): C, 65.51; H, 6.53; N, 14.32; Found (%): C, 65.12; H,6.41; N, 14.10.

EXAMPLE 9a Production of6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazinefumarate

730 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 17ml of tetrahydrofuran; 237 mg of sodium tert-butoxide was added,followed by stirring at an external temperature of 60° C. for 30minutes. After cooling, 347 mg of6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added, followed byrefluxing under heating for 6 hours. After cooling, saline was added;the reaction mixture was extracted with ethyl acetate and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol-triethylamine (50:5:1). The desired fractionwas collected and concentrated under reduced pressure; 470 mg of theresidue was dissolved in ethanol; a solution of 123 mg of fumaric acidin ethanol was added, followed by concentration under reduced pressure.The residue was crystallized from ethanol-ethyl acetate (1:5) and driedto yield 341 mg of the title compound.

Melting point: 114-116° C.; Elemental analysis (for C₃₀H₃₃N₅O₆.0.5H₂O):Calculated (%): C, 63.37; H, 6.03; N, 12.32; Found (%): C, 63.61; H,5.82; N, 12.34.

EXAMPLE 10a Production of6-[6-[4-(Diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazine

Process A: Production of6-(6-Hydroxyhexylamino)[1,2,4]triazolo[4,3-b]pyridazine

In 35 ml of ethanol, 3.55 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazinewas suspended; 6.73 g of 6-aminohexanol was added, followed by refluxingunder heating for 16 hours. After cooling, the reaction mixture wasconcentrated under reduced pressure; the residue was subjected to silicagel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; the precipitatedcrystal was washed with diethyl ether and,dried to yield 5.67 g of thetitle compound.

¹H-NMR (CDCl₃) δ ppm: 1.38-1.80 (8H, m), 3.11 (1H, q, J=6.4 Hz), 3.37(2H, q, J=6.4 Hz), 3.67 (2H, t, J=6.1 Hz), 5.12 (1H, brs), 6.61 (1H, d,J=9.8 Hz), 7.78 (1H, d, J=10.0 Hz), 8.74 (1H, s).

Process B: Production of6-[6-(Methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine

3.26 g of 6-(6-hydroxyhexylamino)[1,2,4]triazolo[4,3-b]pyridazine wassuspended in 60 ml of tetrahydrofuran; 3.59 g of N-ethyldiisopropylamineand 3.17 g of methanesulfonyl chloride were added, followed by stirringat room temperature for 4 hours. Saline was added; the reaction mixturewas extracted with ethyl acetate-tetrahydrofuran (1:1) and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol-triethylamine (50:5:1). The desired fractionwas collected and concentrated under reduced pressure; the precipitatedcrystal was washed with diethyl ether, and dried, to yield 3.24 g of thetitle compound.

Melting point: 103-105° C.; Elemental analysis (for C₁₂H₁₉N₅O₃.0.3H₂O):Calculated (%): C, 45.21; H, 6.20; N, 21.97; Found (%): C, 45.15; H,6.24; N, 21.60.

Process C:

810 mg of6-[6-(methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine wasdissolved in 15 ml of N,N-dimethylformamide; 829 mg of4-(diphenylmethoxy)piperidine, 428 mg of potassium carbonate, and 515 mgof potassium iodide were added, followed by stirring at 60° C. for 4hours. After cooling, saline was added; the reaction mixture wasextracted with ethyl acetate and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; the residue wascrystallized from ethanol-ethyl acetate (1:5), washed with diethylether, recrystallized in the same manner, and dried, to yield 599 mg ofthe title compound.

Melting point: 124-127° C.; Elemental analysis (for C₂₉H₃₆N₆O.0.5H₂O):Calculated (%): C, 70.56; H, 7.55; N, 17.02; Found (%): C, 70.68; H,7.29; N, 17.38.

EXAMPLE 11a Production of6-[6-[4-(Diphenylmethyl)-1-piperazinyl]hexylamino][1,2,4]triazolo[4,3-b]pyridazine

796 mg of6-[6-(methanesulfonyloxy)hexylamino][1,2,4]triazolo[4,3-b]pyridazine wasdissolved in 15 ml of N,N-dimethylformamide; 769 mg of1-(diphenylmethyl)piperazine, 422 mg of potassium carbonate, and 506 mgof potassium iodide were added, followed by stirring at 60° C. for 4hours. After cooling, saline was added; the reaction mixture wasextracted with ethyl acetate and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; the residue wascrystallized from ethyl acetate, washed with diethyl ether,recrystallized in the same manner, and dried, to yield 353 mg of thetitle compound.

Melting point: 133-139° C.; Elemental analysis (for C₂₈H₃₅N₇.0.5H₂O):Calculated (%): C, 70.26; H, 7.58; N, 20.48; Found (%): C, 70.12; H,7.18; N, 20.60.

EXAMPLE 12a Production of3-tert-Butyl-6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazinefumarate

854 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 554 mg of3-tert-butyl-6-chloro[1,2,4]triazolo[4,3-b]pyridazine were dissolved in10 ml of 1-butanol; 0.91 ml of N-ethyldiisopropylamine was added,followed by refluxing under heating for 21 hours. After cooling, ethylacetate was added; the reaction mixture was washed with saturatedaqueous sodium bicarbonate and saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; 780 mg of the residuewas dissolved in ethanol; a solution of 282 mg of fumaric acid inethanol was added, followed by concentration under reduced pressure. Theresidue was crystallized from ethanol-ethyl acetate (1:5), washed withethyl acetate, and dried, to yield 938 mg of the title compound.

¹H-NMR (DMSO-d₆) δ ppm: 1.49 (9H, s), 1.55-2.00 (6H, m), 2.30-2.68 (5H,m), 2.80-2.96 (2H, m), 3.20-3.35 (2H, m), 3.44 (1H, brs), 5.64 (1H,s),6.58 (2H, s), 6.71 (1H, d, J=9.8 Hz), 7.20-7.45 (10H, m), 7.83 (1H, d,J=9.8 Hz). Melting point: 174-176° C.; Elemental analysis (forC₃₄H₄₂N₆O₅.1.5H₂O): Calculated (%): C, 63.63; H, 7.07; N, 13.10; Found(%): C, 64.05; H, 6.58; N, 12.65.

EXAMPLE 13a Production of3-tert-Butyl-6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4.3-b]pyridazine

991 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 20ml of tetrahydrofuran; 322 mg of sodium tert-butoxide was added,followed by stirring at an external temperature of 60° C. for 2 hours.After cooling, 642 mg of3-tert-butyl-6-chloro[1,2,4]triazolo[4,3-b]pyridazine was added,followed by refluxing under heating for 2 hours. After cooling, salinewas added; the reaction mixture was extracted with ethyl acetate anddried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol-triethylamine (50:5:1). Thedesired fraction was collected and concentrated under reduced pressure;1.26 g of the residue was dissolved in 3 ml of pyridine; 1.5 ml ofacetic anhydride was added, followed by stirring at room temperature for6 hours. After the reaction mixture was concentrated under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol-triethylamine (50:5:1). Thedesired fraction was collected and concentrated under reduced pressure;the residue crystallized from ethyl acetate-diethyl ether (1:1), washedwith diethyl ether, and dried, to yield 500 mg of the title compound.

Melting point: 125-127° C.; Elemental analysis (for C₃₀H₃₇N₅O₂):Calculated (%): C, 72.12; H, 7.46; N, 14.02; Found (%): C, 71.93; H,7.47; N, 14.18.

EXAMPLE 14a Production of6-[3-[4-(Diphenylmethoxy)piperidino]-2-hydroxypropoxy][1,2,4]triazolo[4,3-b]pyridazinefumarate

904 mg of 4-(diphenylmethoxy)piperidine and 650 mg of6-(2-oxiranylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine were suspended in25 ml of ethanol, followed by stirring at room temperature for 14 hours,then at 60° C. for 2 hours. After cooling, the ethanol was distilledoff; the residue was subjected to silica gel column chromatography andeluted with ethyl acetate-methanol-triethylamine (50:5:1). The desiredfraction was collected and concentrated under reduced pressure; 1.11 gof the residue was dissolved in ethanol; a solution of 230 mg of fumaricacid in ethanol was added, followed by concentration under reducedpressure. The residue was crystallized from ethanol-ethyl acetate (1:5),washed with ethyl acetate-diethyl ether (1:1), and dried, to yield 591mg of the title compound.

Melting point: 173-175° C.; Elemental analysis (for C₃₀H₃₃N₅O₇):Calculated (%): C, 61.63; H, 5.86; N, 11.98; Found (%): C, 61.87; H,5.90; N, 12.24.

EXAMPLE 15a Production of6-[3-[4-(Diphenylmethyl)-1-piperazinyl]-2-hydroxypropoxy][1,2,4]triazolo[4,3-b]pyridazine

657 mg of 1-(diphenylmethyl)piperazine and 500 mg of6-(2-oxylanylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine were suspended in20 ml of ethanol, followed by stirring at room temperature for 1 day.The precipitated crystal was collected by filtration and washed withdiethyl ether. The filtrate was distilled under reduced pressure; theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol (10:1). The desired fraction was collectedand concentrated under reduced pressure; the concentrate was combinedwith the previously collected crystal, crystallized frommethanol-ethanol (1:5), washed with ethyl acetate-diethyl ether (1:1),and dried, to yield 269 mg of the title compound.

Melting point: 95-97° C.; Elemental analysis (for C₂₅H₂₈N₆O₂):Calculated (%): C, 63.68; H, 6.63; N, 17.82; Found (%): C, 64.05; H,6.53; N, 17.76.

EXAMPLE 16a Production of2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrileHydrochloride

6.55 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 100ml of tetrahydrofuran; 2.12 g of sodium tert-butoxide was added,followed by stirring at an external temperature of 60° C. for 40minutes. After cooling, 4.86 g of2-[6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-2-methylpropionitrilewas added, followed by refluxing under heating for 5 hours. Aftercooling, saline was added; the reaction mixture was extracted with ethylacetate, washed with saturated saline, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; in 7.90 g of theresidue was dissolved in 5 ml of pyridine; 5 ml of acetic anhydride wasadded, followed by stirring at room temperature for 15 hours. Aftersaline was added, the reaction mixture was extracted with ethyl acetate,washed with saturated saline, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and extracted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; the residue (6.26 g)was dissolved in ethanol; 1.52 ml of a 4 N solution of hydrogen chloridein ethyl acetate was added, followed by concentration under reducedpressure. The residue was crystallized from methanol-ethanol (1:5),washed with ethanol-ethyl acetate (1:5), and dried, to yield 5.19 g ofthe title compound.

Melting point: 205-207° C.; Elemental analysis (forC₃₀H₃₅N₆O₂Cl.0.5H₂O): Calculated (%): C, 64.80; H, 6.52; N, 15.11; Found(%): C, 65.02; H, 6.28; N, 15.13.

EXAMPLE 17a Production of Ethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionatefumarate

5.01 g of2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrilewas dissolved in 20 ml of ethanol; 20 ml of a 2 N aqueous solution ofsodium hydroxide was added, followed by refluxing under heating for 8hours. After cooling, the ethanol was distilled off; 2 N hydrochloricacid was added to reach pH 5; sodium chloride was added; the reactionmixture was extracted with tetrahydrofuran and dried over magnesiumsulfate. After concentration under reduced pressure, 2.18 g of thecarboxylic acid obtained was dissolved in 20 ml ofN,N-dimethylformamide; 0.85 ml of N-ethyldiisopropylamine was added.After stirring at room temperature for 5 minutes, 0.40 ml of iodoethanewas added, followed by stirring at room temperature for 5 hours. Aftersaline was added, the reaction mixture was extracted with ethylacetate-tetrahydrofuran (1:1) and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; 750 mg of the residuewas dissolved in ethanol; a solution of 156 mg of fumaric acid inethanol was added, followed by concentration under reduced pressure. Theresidue was crystallized from ethyl acetate-hexane (1:1), washed withdiethyl ether-hexane (1:1), and dried, to yield 648 mg of the titlecompound.

Melting point: 173-175° C.; Elemental analysis (for C₃₆H₄₃N₅O₈.H₂O):Calculated (%): C, 62.50; H, 6.56; N, 10.12; Found (%): C, 62.24; H,6.25; N, 9.78.

EXAMPLE 18a Production of2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrilefumarate

5.57 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 3.62 g of2-[6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrilewere dissolved in 60 ml of 1-butanol; 5.65 ml of N-ethyldiisopropylaminewas added, followed by refluxing under heating for 3.5 hours. Aftercooling, ethyl acetate was added; the reaction mixture was washed withsaturated aqueous sodium bicarbonate, washed with saturated saline, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol-triethylamine (50:5:1). Thedesired fraction was collected and concentrated under reduced pressure;7.18 g of the residue was dissolved in ethanol; a solution of 1.59 g offumaric acid in ethanol was added, followed by concentration underreduced pressure. The residue was powdered from diethyl ether and driedto yield 7.71 g of the title compound.

Amorphous

Elemental analysis (for C₃₄H₃₉N₇O₅.0.5H₂O.0.5Et₂O): Calculated (%): C,64.36; H, 6.75; N, 14.60; Found (%): C, 64.00; H, 6.69; N, 14.65.

EXAMPLE 19a Production of2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionicAcid

6.16 g of2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrilewas dissolved in 30 ml of ethanol; 30 ml of a 2 N aqueous solution ofsodium hydroxide was added, followed by refluxing under heating for 1.5days. After cooling, the ethanol was distilled off; the residue waswashed with ethyl acetate; 1 N hydrochloric acid was added to reach pH5; sodium chloride was added; the reaction mixture was extracted withtetrahydrofuran and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was powdered from ethylacetate-diethyl ether (1:1); the powder was collected by filtration,washed with ethyl acetate-diethyl ether (1:1), and dried, to yield 1.04g of the title compound.

¹H-NMR (DMSO-d₆-CDCl₃ (3:1)) δ ppm: 1.59 (6H, s), 1.50-2.05 (6H, m),2.40-2.65 (5H, m), 2.91 (2H, br), 3.19 (2H, br), 5.61 (1H, s), 6.69 (1H,d, J=10.0 Hz), 7.18-7.42 (10H, m), 7.76 (1H, d, J=10.0 Hz). Meltingpoint: 155-157° C.; Elemental analysis (for C₃₀H₃₆N₆O₃.H₂O): Calculated(%): C, 65.91; H, 7.01; N, 15.37; Found (%): C, 66.28; H, 7.16; N,14.88.

EXAMPLE 20a Production of Ethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionatefumarate

4.98 g of2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionicacid was dissolved in 50 ml of N,N-dimethylformamide; 1.95 ml ofN-ethyldiisopropylamine was added. After stirring at room temperaturefor 10 minutes, 0.90 ml of iodoethane was added, followed by stirring atroom temperature for 8.5 hours; 0.90 ml of iodoethane and 1.95 ml ofN-ethyldiisopropylamine were added, followed by stirring at roomtemperature for 17 hours. After ice water was added, the reactionmixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and driedover magnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol-triethylamine (50:5:1). The desired fractionwas collected and concentrated under reduced pressure; 531 mg of theresidue was dissolved in ethanol; a solution of 111 mg of fumaric acidin ethanol was added, followed by concentration under reduced pressure.The residue was powdered from diethyl ether; the powder was collected byfiltration and dried to yield 563 mg of the title compound.

Melting point: 97-99° C.; Elemental analysis (for C₃₆H₄₄N₆O₇.H₂O):Calculated (%): C, 62.59; H, 6.71; N, 12.17; Found (%): C, 62.70; H,6.90; N, 11.97.

EXAMPLE 21a Production of Ethyl6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate

5.15 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 3.6 g of ethyl6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate were dissolved in70 ml of N,N-dimethylformamide; 5.48 ml of N-ethyldiisdpropylamine wasadded, followed by stirring under heating at an external temperature of70° C. for 4 hours. After cooling, cold saline was added; the reactionmixture was extracted with tetrahydrofuran and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; half of theprecipitated crystal was recrystallized from ethanol-ethyl acetate(1:1), collected by filtration, and dried, to yield 2.13 g of the titlecompound.

Melting point: 129-133° C.; Elemental analysis (for C₂₉H₃₄N₆O₃.0.3H₂O):Calculated (%): C, 66.98; H, 6.71; N, 16.16; Found (%): C, 67.09; H,6.88; N, 16.02.

EXAMPLE 22a Production of6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylicAcid

1.31 g of ethyl6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylatewas dissolved in 8 ml of ethanol; 8 ml of a 1 N aqueous solution ofsodium hydroxide was added, followed by refluxing under heating for 3hours. After cooling, the ethanol was distilled off; the residue waswashed with ethyl acetate; 1 N hydrochloric acid was added to reach pH5. The precipitated crystal was collected by filtration, washed withwater and ethyl acetate, and dried, to yield 1.19 g of the titlecompound.

Melting point: 102-104° C.; Elemental analysis (for C₂₇H₃₀N₆O₃.2H₂O):Calculated (%): C, 62.05; H, 6.56; N, 16.00; Found (%): C, 61.82; H,6.40; N, 16.06.

EXAMPLE 23a Production of2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionamide

409 mg of2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionitrilewas dissolved in 6 ml of 2-propanol; 3.5 ml of a 1 N aqueous solution ofsodium hydroxide was added, followed by stirring under heating at anexternal temperature of 40° C. for 12 hours. After cooling, the2-propanol was distilled off; the residue was extracted with ethylacetate-tetrahydrofuran (1:1), washed with saturated saline, and driedover magnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol-triethylamine (50:5:1). The desired fractionwas collected and concentrated under reduced pressure; the residue wascrystallized from ethyl acetate-diethyl ether (1:1), washed with diethylether, and dried, to yield 293 mg of the title compound.

Melting point: 133-136° C.; Elemental analysis (for C₃₀H₃₆N₆O₃.0.5H₂O):Calculated (%): C, 67.02; H, 6.94; N, 16.63; Found (%): C, 67.17; H,6.84; N, 16.35.

EXAMPLE 24a Production of2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3-yl]-2-methylpropionamideHydrochloride

644 mg of2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-,3-yl]-2-methylpropionicacid was dissolved in 6 ml of N,N-dimethylformamide; under ice cooling,474 mg of N,N′-carbonyldiimidazole was added. After stirring at roomtemperature for 4 hours, 134 mg of ammonium chloride was added under icecooling, followed by stirring at room temperature for 2 hours. After icewater was added, the reaction mixture was extracted with ethylacetate-tetrahydrofuran (1:1), washed with saturated saline, and driedover magnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate. The desired fraction was collected and concentratedunder reduced pressure; the residue was dissolved in ethanol; 0.30 ml ofa 4 N solution of hydrogen chloride in ethyl acetate was added, followedby concentration under reduced pressure. The residue was crystallizedfrom ethanol-acetone (1:5) and dried to yield 301 mg of the titlecompound.

Melting point: 226-227° C.; Elemental analysis (forC₃₀H₃₈N₇O₂Cl.0.3H₂O): Calculated (%): C, 63.26; H, 6.83; N, 17.21; Found(%): C, 63.27; H, 6.68; N, 17.11.

EXAMPLE 25a Production ofN-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycineEthyl Ester

1.25 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.20 g ofN-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycineethyl ester were dissolved in 20 ml of N,N-dimethylformamide; 1.33 ml ofN-ethyldiisopropylamine was added, followed by stirring under heating atan external temperature of 60° C. for 7.5 hours. After cooling, coldaqueous sodium bicarbonate was added; the reaction mixture was extractedwith ethyl acetate, washed with saturated saline, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was subjected to silica gel column chromatography and elutedwith ethyl acetate-methanol-triethylamine (50:5:1). The desired fractionwas collected and concentrated under reduced pressure; the precipitatedcrystal was recrystallized from ethanol-ethyl acetate fir (1:3),collected by filtration, and dried, to yield 1.17 g of the titlecompound.

Melting point: 165-167° C.; Elemental analysis (for C₃₃H₄₁N₇O₄):Calculated (%): C, 66.09; H, 6.89; N, 16.35; Found (%): C, 65.91; H,6.76; N, 16.44.

EXAMPLE 26a Production ofN-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycine

830 mg ofN-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycineethyl ester was dissolved in 10 ml of ethanol; 3.2 ml of a 1 N aqueoussolution of sodium hydroxide was added, followed by stirring at roomtemperature for 17 hours. After the ethanol was distilled off, 1 Nhydrochloric acid was added to reach pH 4.5. The precipitated crystalwas collected by filtration, washed with water and ethanol, and dried,to yield 610 mg of the title compound.

Melting point: 191-193° C.; Elemental analysis (for C₃₁H₃₇N₇O₄.1.5H₂O):Calculated (%): C, 62.19; H, 6.73; N, 16.38; Found (%): C, 62.48; H,6.72; N, 16.53.

EXAMPLE 27a Production ofN-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycineethyl ester difumarate

1.04 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 14ml of N,N-dimethylformamide; 141 mg of sodium hydride (60% in oil) wasadded, followed by stirring at room temperature under reduced pressurefor 50 minutes. Under ice cooling, 1.00 g ofN-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycineethyl ester was added, followed by stirring at ice temperature for 1hour, then at room temperature for 2 hours. After saline was added, thereaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1)and dried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol-triethylamine (50:5:1). Thedesired fraction was collected and concentrated under reduced pressure;1.62 g of the residue was dissolved in 2 ml of pyridine; 1 ml of aceticanhydride was added, followed by stirring at room temperature for 15hours. After saline was added, the reaction mixture was extracted withethyl acetate, washed with saturated saline, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (50:5:1). The desired fraction wascollected and concentrated under reduced pressure; 1.32 g of the residuewas dissolved in ethanol; a solution of 511 mg of fumaric acid inethanol was added, followed by concentration under reduced pressure. Theresidue was powdered from diethyl ether and dried to yield 1.53 g of thetitle compound.

Amorphous

Elemental analysis (for C₄₁H₄₈N₆O₁₃): Calculated (%): C, 59.13; H, 5.81;N, 10.09; Found (%): C, 59.15; H, 5.97; N, 10.16.

EXAMPLE 28a Production ofN-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycine

690 mg ofN-[6-[3-[4-(diphenylinethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]-2,2-dimethylglycineethyl ester was dissolved in 8 ml of tetrahydrofuran; 1.3 ml of a 1 Naqueous solution of sodium hydroxide was added, followed by stirring atroom temperature for 19 hours. The tetrahydrofuran was distilled off; 1N hydrochloric acid was added to reach pH 5. Saturated saline was added;the reaction mixture was extracted with tetrahydrofuran and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crystal was washed with ethyl acetate and dried to yield459 mg of the title compound.

Melting point: 163-165° C.; Elemental analysis (for C₃₁H₃₆N₆O₅.3H₂O):Calculated (%): C, 59.41; H, 6.75; N, 13.41; Found (%): C, 59.04; H,6.39; N, 13.27.

EXAMPLE 29a Production ofN-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]glycineethyl ester

1.58 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g ofN-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)glycine ethylester were dissolved in 15 ml of N,N-dimethylformamide; 1.68 ml ofN-ethyldiisopropylamine was added, followed by stirring under heating atan external temperature of 70° C. for 5 hours. After cooling, water wasadded; the reaction mixture was extracted with tetrahydrofuran. Afterconcentration under reduced pressure, the precipitated crystal was twicerecrystallized from ethanol-tetrahydrofuran (1:1), collected byfiltration, and dried, to yield 995 mg of the title compound.

Melting point: 152-155° C.; Elemental analysis (for C₃₁H₃₇N₇O₄.0.5H₂O):Calculated (%): C, 64.12; H, 6.60; N, 16.88; Found (%): C, 64.10; H,6.55; N, 16.87.

EXAMPLE 30a Production ofN-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]glycine

1.29 g ofN-[6-(3-[4-(diphenylmethoxy)piperidino]propylamino)[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl]glycineethyl ester was dissolved in 10 ml of ethanol; 4.5 ml of a 1 N aqueoussolution of sodium hydroxide was added, followed by stirring at roomtemperature for 30 minutes. The ethanol was distilled off under reducedpressure; the reaction mixture was adjusted to pH 4.5 using 1 Nhydrochloric acid. The precipitated crystal was collected by filtration,washed with water and acetone, and dried, to yield 831 mg of the titlecompound.

Melting point: 182-184° C.; Elemental analysis (for C₂₉H₃₃N₇O₄.H₂O):Calculated (%): C, 62.02; H, 6.28; N, 17.46; Found (%): C, 62.32; H,6.10; N, 17.46.

PREPARATION EXAMPLE 1a

(1) Compound of Example 22a 10.0 mg

(2) Lactose 60.0 mg

(3) Corn starch 35.0 mg

(4) Gelatin 3.0 mg

(5) Magnesium stearate 2.0 mg

A mixture of 10.0 mg of the compound obtained in Example 22a, 60.0 mg oflactose and 35.0 mg of corn starch was granulated through a sieve of 1mm mesh, using 0.03 ml of a 10% aqueous solution of gelatin (containing3.0 mg of gelatin), after which it was dried at 40° C. and again sieved.The resulting granules were mixed with 2.0 mg of magnesium stearate,followed by compression. The resulting core tablets were coated with asugar coat, using an aqueous suspension of sucrose, titanium dioxide,talc and gum arabic. The coated tablets were polished with beeswax toyield finished coated tablets.

PREPARATION EXAMPLE 2a

(1) Compound of Example 22a 10.0 mg

(2) Lactose 70.0 mg

(3) Corn starch 50.0 mg

(4) Soluble starch 7.0 mg

(5) Magnesium stearate 3.0 mg

After 10.0 mg of the compound obtained in Example 22a and 3.0 mg ofmagnesium stearate were granulated using 0.07 ml of an aqueous solutionof soluble starch (containing 7.0 mg of soluble starch), the resultinggranules were dried and mixed with 70.0 mg of lactose and 50.0 mg ofcorn starch. The mixture was compressed to yield tablets.

PREPARATION EXAMPLE 3a

(1) Compound of Example 22a 5.0 mg

(2) Sodium chloride 20.0 mg

(3) Distilled water was added to reach a total volume of 2 ml.

5.0 mg of the compound obtained in Example 22a and 20.0 mg of sodiumchloride were dissolved in distilled water and diluted with water toreach a total volume of 2.0 ml. The resulting solution was filtered andaseptically packed in a 2 ml ampule. After sterilization, the ampule wassealed to yield a solution for injection.

EXPERIMENTAL EXAMPLE 1a Effect on Histamine-induced Skin Reactions inGuinea Pigs

Male Hartley guinea pigs weighing about 500 g were used. After thedorsal hair was shaved under ether anesthesia, 1 ml of a 2.5% pontaminesky blue solution was injected intravenously administered, and then 0.1ml of histamine at 3 μg/ml was injected intradermally into 2 sites (leftand right) in the back. Thirty minutes after the injection of histamine,the animals were killed by bleeding and the skin was removed. Twoperpendicular diameters (mm) of each blue spot on the inside of the skinwere measured and multiplied; the mean for the two products was taken asthe microvascular permeability index. Test compounds were suspended in a5% gum arabic solution and orally administered in a volume of 0.2 ml/100g body weight 1 hour before histamine administration. Animals in thecontrol group received the same volume of a 5% gum arabic solution. Thesuppression rate of the sample for the title reaction was calculatedusing Equation 1, and the results are given in Table 1.

Inhibition (%) of histamine-induced skin reactions=100×(1−vascularpermeability index in the presence of drug/vascular permeability indexin control group)  Equation 1

TABLE 1 Effects of Test Compounds on Histamine-induced Skin VascularPermeability Suppression (%) of histamine-induced skin vascularpermeability elevation, Compound oral administration at 3 mg/kg Example7a 89 Example 10a 91 Example 13a 79 Example 22a 86

EXPERIMENTAL EXAMPLE 2a

1) Preparation of Guinea Pig Eosinophils

To male Hartley guinea pigs, 2 ml of equine serum (Bio-Whittaker, Inc.)was intraperitoneally administered once weekly for 8 consecutive weeks.At 48 hours after final administration, 75 ml of physiological salinewas intraperitoneally injected, after which the saline was recovered andcentrifuged at 400×g for 5 minutes. The resulting sediment was suspendedin 5 ml of Percoll solution (density (d)=1.07) and layered on top of themultiple layers of different densities of Percoll solution(density(d)=1.112, 5 ml; d=1.095, 10 ml; d=1.090, 10 ml; d=1.085, 5 ml),followed by centrifugation at 1,000×g for 25 minutes (20° C.). The celllayer formed at the interface between densities 1.112 and 1.095 wascollected. Erythrocytes present in the collected cell sediment wereremoved by hypotonic treatment (suspended in water for 30 minutes).

The cell sediment was washed 3 times with Hanks' solution containing 10mM Hepes (Dojin Kagaku) (Hanks-Hepes) and suspended in a Hanks-Hepessolution containing 2% human serum albumin (Wako Pure Chemical Industryor Sigma) (Hanks-Hepes-HSA) to a final concentration of 5.56×10⁶cells/ml. Eosinophil purity was 90%, viability being over 98%.

2) Determination of Chemotactic Reaction Suppression

To a 24-well petri dish, which serves as a lower chamber, 600 μl ofHanks-Hepes-HSA solution containing LTB₄ (final concentration 10⁻⁸ M,Cascade Biochemical Ltd.), was transferred, followed by incubation at37° C. for 30 minutes in a carbon dioxide incubator. Separately, 200 μlof eosinophil suspension (5×10⁶ cells/ml), previously incubated at 37 Cfor 15 minutes, was added to Chemotaxicell (polycarbonate membrane, poresize 3 μm, thickness 10 μm), which serves as an upper chamber, after theupper chamber was attached to the 24-well petri dish. After 2 hours ofreaction in the CO₂ incubator, the Chemotaxicell was removed; 60 μl of a2% (w/v) solution of EDTA in physiological saline was added to theliquid in the lower chamber. After the mixture was on cooled ice, thecells migrating into the lower chamber were counted using a blood cellcounter [Coulter Counter (trade name)]. The test drug, dissolved inN,N-dimethyl formamide (DMF), was added to both the upper and lowerchambers to a final concentration of 10-5 M.

Chemotactic reaction suppression rate=[1−(number of migrating cells inthe presence of drug/number of migrating cells in the absence ofdrug).]×100  Equation 2

Suppression rates of LTB₄-induced chemotactic reaction by testsubstances (1×10⁻⁵ M) were calculated using the above equation. Theresults are shown in Table 2.

TABLE 2 Action on LTB₄-induced Chemotactic Reaction in Guinea PigEosinophils Compound Suppression rate (%) Example 7a 36 Example 10a 60Example 13a 41 Example 22a 50

COMPOUND (Ib): REFERENCE EXAMPLE 1b Production of4-(Diphenylmethoxy)-1-piperidinepropanol

2.67 g of 4-diphenylmethoxypiperidine was dissolved in 20 ml ofN,N-dimethylformamide; 1.09 ml of 3-bromopropanol and 1.66 g ofpotassium carbonate were added, followed by stirring at room temperaturefor 40 hours. After ice water was poured, the reaction mixture wasextracted with ethyl acetate; the extract was washed with saline anddried over magnesium sulfate. After concentration under reducedpressure, the residue was subjected to silica gel column chromatographyand eluted with ethyl acetate-methanol-triethylamine (90:10:1). Thedesired fraction was collected and concentrated to yield 2.32 g of thetitle compound.

¹H-NMR (CDCl₃) δ ppm: 1.60-1.95 (6H, m), 2.10-2.35 (2H, m), 2.58 (2H, t,J=5 Hz), 2.75-2.90 (2H, m), 3.3-3.6 (1H, m), 3.78 (2H, t, J=5 Hz), 5.50(1H, s), 7.1-7.5 (10H, m).

REFERENCE EXAMPLE 2b Production of6-Chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.853 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one wasdissolved in 5 ml of N,N-dimethylformamide; 0.83 g of potassiumcarbonate was added; with stirring at room temperature, 0.5 ml of methyliodide was added. After stirring at room temperature for 15 hours, icewater and saline were added; the reaction mixture was extracted withethyl acetate-tetrahydrofuran (1:1); the extract was washed with salineand dried over magnesium sulfate. After concentration under reducedpressure, the crystal obtained was collected by filtration, washed withdiethyl ether, and dried, to yield 0.62 g of the title compound.

Melting point: 176-177° C.; Elemental analysis (for C₆H₅N₄OCl):Calculated (%): C, 39.04; H, 2.73; N, 30.75; Found (%): C, 38.98; H,2.67; N, 30.75.

REFERENCE EXAMPLE 3b Production of6-Chloro-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.341 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one and 0.669 gof chlorotriphenylmethane were dissolved in 5 ml ofN,N-dimethylformamide; 0.414 ml of N-ethyldiisopropylamine was added,followed by stirring at room temperature for 2 days. After water wasadded, the reaction mixture was extracted with ethyl acetate; theextract was washed with saline and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with hexane-ethyl acetate(2:1). The desired fraction was collected and concentrated; the crystalobtained was collected by filtration, washed with diethyl ether, anddried, to yield 0.591 g of the title compound.

Melting point: 246-247° C.; Elemental analysis (for C₂₄H₁₇N₄OCl):Calculated (%): C, 69.82; H, 4.15; N, 13.57; Found (%): C, 69.31; H,4.33; N, 13.07.

EXAMPLE 1b Production of6-[3-[4-(Diphenylmethoxy)piperidino]propylamino]-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.277 g of 6-chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas dissolved in 2 ml of N,N-dimethylformamide; 0.487 g of4-(diphenylmethoxy)-1-piperidinepropanamine was added, followed bystirring in an oil bath (bath temperature 140-150° C.) for 1 hour. Aftercooling, ice water and an aqueous solution of sodium hydrogen carbonatewere added; the reaction mixture was extracted with ethyl acetate; theextract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (90:10:1). The desired fraction wascollected and concentrated; the crystal obtained was filtered, washedwith diethyl ether, and dried, to yield 0.19 g of the title compound.

Melting point: 171-172° C.; Elemental analysis (for C₂₁H₃₂N₆O₂):Calculated (%): C, 68.62; H, 6.82; N, 17.78; Found (%): C, 68.51; H,6.72;N, 17.75.

EXAMPLE 2b Production of6-[3-[4-(Diphenylmethoxy)piperidino]propoxy]-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.52 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 3 mlof N,N-dimethylformamide; 0.0704 g of 60% oily sodium hydride was added,followed by stirring at room temperature for 1 hour. 0.325 g of6-chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was added,followed by stirring at room temperature for 2 hours. After ice waterwas added, the reaction mixture was extracted with ethyl acetate; theextract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (90:10:1). The desired fraction wascollected and concentrated; the crystal obtained was filtered, washedwith diethyl ether, and dried, to yield 0.502 g of the title compound.

Melting point: 139-140° C.; Elemental analysis (for C₂₇H₃₁N₅O₃):Calculated (%): C, 68.48; H, 6.60; N, 14.79; Found (%): C, 68.32; H,6.59; N, 14.58.

EXAMPLE 3b Production of6-[3-[4-(Diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.512 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one wasdissolved in 15 ml of n-butanol; 0.88 g of4-(diphenylmethoxy)-1-piperidinepropanamine and 1.04 ml ofN-ethyldiisopropylamine were added, followed by refluxing under heatingin an oil bath for 5 hours. After cooling, the n-butanol was mostlydistilled off under reduced pressure; to the residue, an aqueoussolution of sodium hydrogen carbonate was added; the reaction mixturewas extracted with ethyl acetate; the extract was washed with saturatedsaline and dried over magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(85:15:1). The desired fraction was collected and concentrated; thecrystal obtained was filtered, washed with diethyl ether, and dried, toyield 0.35 g of the title compound.

Melting point: 156-170° C.; Elemental analysis (for C₂₆H₃₀N₆O₂.2H₂O):Calculated (%): C, 65.52; H, 6.72; N, 17.64; Found (%): C, 65.78; H,6.71; N, 17.52.

EXAMPLE 4b Production of6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.326 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 3ml of N,N-dimethylformamide; 0.044 g of 60% oily sodium hydride wasadded, followed by stirring at room temperature for 1 hour. 0.326 g of6-chloro-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one wasadded, followed by stirring at room temperature for 14 hours. After icewater was added, the reaction mixture was extracted with ethyl acetate;the extract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol (95:5). The desired fraction was collected andconcentrated to yield 0.58 g of6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-oneas an oily substance. 0.58 g of the oily substance obtained wasdissolved in 10 ml of acetone; 467 mg of p-toluenesulfonic acid hydratewas added, followed by refluxing under heating in an oil bath for 5hours. After cooling, the acetone was mostly distilled off under reducedpressure; to the residue, an aqueous solution of sodium hydrogencarbonate was added; the reaction mixture was extracted with ethylacetate-tetrahydrofuran (2:1); the extract was washed with saturatedsaline and dried over magnesium sulfate. After concentration underreduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(85:15:1). The desired fraction was collected and concentrated; thecrystal obtained was filtered, washed with ethyl acetate, and dried, toyield 0.137 g of the title compound.

Melting point: 209-211° C.; Elemental analysis (for C₂₆H₂₉N₅O₃):Calculated (%): C, 67.96; H, 6.36; N, 15.24; Found (%): C, 67.72; H,6.16; N, 15.09.

EXAMPLE 5b Production of Ethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]acetate

0.459 g of6-(3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas suspended in 6 ml of N,N-dimethylformamide; 0.048 g of 60% oilysodium hydride was added, followed by stirring at room temperature for 1hour. Under ice cooling, 0.133 ml of ethyl bromoacetate was added,followed by stirring at room temperature for 4 hours. After ice waterwas added, the reaction mixture was extracted with ethyl acetate; theextract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (185:15:2). The desired fraction wascollected and concentrated; the crystal obtained was filtered, washedwith diethyl ether, and dried, to yield 0.235 g of the title compound.

Melting point: 124-125° C.; Elemental analysis (for C₃₀H₃₅N₅O₅):Calculated (%): C, 66.04; H, 6.47; N, 12.84; Found (%): C, 65.82; H,6.40; N, 12.81.

EXAMPLE 6b Production of Ethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateHydrochloride

0.459 g of6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas suspended in 6 ml of N,N-dimethylformamide; 0.048 g of 60% oilysodium hydride was added, followed by stirring at room temperature for30 minutes. 0.294 ml of ethyl 2-bromoisobutyrate was added, followed bystirring in an oil bath (bath temperature 110° C.) for 4 hours. Aftercooling, 0.048 g of 60% oily sodium hydride and 0.294 ml of ethyl2-bromoisobutyrate were added, followed.by stirring in an oil bath (bathtemperature 110° C.) for 10 hours. After cooling, ice water was added;the reaction mixture was extracted with ethyl acetate; the extract waswashed with saturated saline and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (185:15:2). The desired fraction wascollected and concentrated to yield 0.401 g of ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateas an oily substance. This oily substance was dissolved in 5 ml of ethylacetate; 0.5 ml of a 4 N solution of hydrogen chloride in ethyl acetatewas added, followed by concentration; the residue was powdered fromdiethyl ether; the powder was collected by filtration and dried to yield0.300 g of the title compound.

Melting point: 129° C. (softened); Elemental analysis (forC₃₂H₃₉N₅O₅.HCl.H₂O): Calculated (%): C, 61.19; H, 6.74; N, 11.15; Found(%): C, 61.37; H, 6.75; N, 11.21.

EXAMPLE 7b Production of ethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]acetate

0.550 g of6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas suspended in 3 ml of N,N-dimethylformamide; 0.058 g of 60% oilysodium hydride was added, followed by stirring at room temperature for 1hour. Under ice cooling, 0.160 ml of ethyl bromoacetate was added,followed by stirring at room temperature for 2 hours. After ice waterwas added, the reaction mixture was extracted with ethyl acetate; theextract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wassubjected to silica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (90:10:1). The desired fraction wascollected and concentrated; the crystal obtained was filtered, washedwith diethyl ether, and dried, to yield 0.332 g of the title compound.

Melting point: 137-139° C.; Elemental analysis (for C₃₀H₃₆N₆O₄):Calculated (%): C, 66.15; H, 6.66; N, 15.43; Found (%): C, 65.98; H,6.54; N, 15.33.

EXAMPLE 8b Production of Ethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateHydrochloride

0.606 g of6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas suspended in 3 ml of N,N-dimethylformamide; 0.063 g of 60% oilysodium hydride was added,-followed by stirring at room temperature for 1hour. 0.253 ml of ethyl 2-bromoisobutyrate was added, followed bystirring in an oil bath (bath temperature 80° C.) for 17 hours. Aftercooling, 0.063 g of 60% oily sodium hydride and 0.253 ml of ethyl2-bromoisobutyrate were added, followed by stirring in an oil bath (bathtemperature 80° C.) for 3 hours. After cooling, ice water was added; thereaction mixture was extracted with ethyl acetate; the extract waswashed with saturated saline and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was subjected tosilica gel column chromatography and eluted with ethylacetate-methanol-triethylamine (90:10:1). The desired fraction wascollected and concentrated to yield 0.38 g of ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateas an oily substance. This oily substance was dissolved in 5 ml of ethylacetate; 0.5 ml of a 4 N solution of hydrogen chloride in ethyl acetatewas added, followed by concentration; the residue was powdered fromdiethyl ether, collected by filtration, and dried, to yield 0.342 g ofthe title compound.

Melting point: 162° C.; Elemental analysis (forC₃₂H₄₀N₆O₄.HCl.(C₂H₅)₂O): Calculated (%): C, 61.83; H, 7.35; N, 12.02;Found (%): C, 62.16; H, 7.02; N, 12.15.

EXAMPLE 9b Production of2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionicAcid

0.50 g of ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionatewas dissolved in 3 ml of ethanol; 2.2 ml of a 1 N aqueous solution ofsodium hydroxide was added, followed by stirring at room temperature for24 hours. After the ethanol was distilled off under reduced pressure,the residue was diluted with water and washed with ethyl acetate. To thewater layer, 2.2 ml of 1 N hydrochloric acid was added; the mixture wassaturated with sodium chloride and extracted with ethylacetate-tetrahydrofuran (2:1); the extract was washed with saturatedsaline and dried over magnesium sulfate. After concentration underreduced pressure, the residue was powdered by the addition of ethylacetate, collected by filtration, washed with ethyl acetate, and dried,to yield 0.203 g of the title compound.

Melting point: 181-185° C.; Elemental analysis (for C₃₀H₃₆N₆O₄.2.5H₂O):Calculated (%): C, 61.10; H, 7.01; N, 14.25; Found (%): C, 61.31; H,7.02; N, 13.91.

EXAMPLE 10b Production of6-[3-[4-(Diphenylmethoxy)piperidino]propylamino]-2-(pivaloyloxymethyl)[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.560 g of6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas suspended in 3 ml of N,N-dimethylformamide; 0.210 g of potassiumcarbonate and 0.220 ml of chloromethyl pivalate were added, followed bystirring at room temperature for 15 hours. After ice water was added,the reaction mixture was extracted with ethyl acetate; the extract waswashed with saline and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(185:15:2). The desired fraction was collected and concentrated; thecrystal obtained was filtered, washed with diethyl ether, and dried, toyield 0.39 g of the title compound.

Melting point: 168-171° C.; Elemental analysis (for C₃₂H₄₀N₆O₄):Calculated (%): C, 67.11; H, 7.04; N, 14.67; Found (%): C, 67.01; H,6.79; N, 14.75.

EXAMPLE 11b Production of pivaloyloxymethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate

0.750 g of ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionatewas dissolved in 5 ml of ethanol; 3.28 ml of a 1 N aqueous solution ofsodium hydroxide was added, followed by stirring at room temperature for24 hours. After the ethanol was distilled off under reduced pressure,the residue was diluted with water and washed with ethyl acetate; to thewater layer, 3.28 ml of 1 N hydrochloric acid was added; the reactionmixture was extracted with ethyl acetate-tetrahydrofuran (1:1); theextract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasdissolved in 5 ml of N,N-dimethylformamide; 0.273 g of potassiumcarbonate and 0.285 ml of chloromethyl pivalate were added, followed bystirring at room temperature for 15 hours. After ice water was added,the reaction mixture was extracted with ethyl acetate; the extract waswashed with saline and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(185:15:2). The desired fraction was collected and concentrated; theresidue was crystallized from diethyl ether, collected by filtration,and dried, to yield 0.524 g of the title compound.

Melting point: 162° C.; Elemental analysis (for C₃₆H₄₆N₆O₆): Calculated(%): C, 65.63; H, 7.04; N, 12.76; Found (%): C, 65.52; H, 6.80; N,12.86.

EXAMPLE 12b Production of pivaloyloxymethyl2-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateFumarate

0.750 g of ethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionatewas dissolved in 6 ml of ethanol; 3.9 ml of a 1 N aqueous solution ofsodium hydroxide was added, followed by stirring at room temperature for40 hours. After the ethanol was distilled off under reduced pressure,the residue was diluted with water and washed with ethyl acetate; to thewater layer, 3.9 ml of 1 N hydrochloric acid was added; the reactionmixture was extracted with ethyl acetate-tetrahydrofuran (1:1); theextract was washed with saturated saline and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasdissolved in 5 ml of N,N-dimethylformamide; 0.324 g of potassiumcarbonate and 0.339 ml of chloromethyl pivalate were added, followed bystirring at room temperature for 18 hours. After ice water was added,the reaction mixture was extracted with ethyl: acetate; the extract waswashed with saline and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol (95:5). Thedesired fraction was collected and concentrated to yield 0.50 g ofpivaloyloxymethyl2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionateas an oily substance. 0.50 g of this oily substance was dissolved in 5ml of ethyl acetate; a solution of 87 mg of fumaric acid in 3 ml ofmethanol was added, followed by concentration under reduced pressure.The residue was crystallized from ethyl acetate, collected byfiltration, and dried to yield 15 0.463 g of the title compound.

Melting point: 160-162° C.; Elemental analysis (for C₄₀H₄₉N₅O₁₁.0.5H₂O):Calculated (%): C, 61.21; H, 6.42; N, 8.92; Found (%): C, 61.37; H,6.50; N, 8.88.

EXAMPLE 13b Production of6-[3-[4-(Diphenylmethoxy)piperidino]propoxy]-2-(pivaloyloxymethyl)[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one

0.552 g of6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-onewas suspended in 3 ml of N,N-dimethylformamide; 0.200 g of potassiumcarbonate and 0.209 ml of chloromethyl pivalate were added, followed bystirring at room temperature for 20 hours. After ice water was added,the reaction mixture was extracted with ethyl acetate; the extract waswashed with saline and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was subjected to silica gel columnchromatography and eluted with ethyl acetate-methanol-triethylamine(185:15:2). The desired fraction was collected and concentrated; thecrystal obtained was filtered, washed with siethyl ether-hexane (1:1),and dried, to yield 0.515 g of the title compound.

Melting point: 108-110° C.; Elemental analysis (for C₃₂H₂₉N₅O₅):Calculated (%): C, 67.00; H, 6.85; N, 12.21; Found (%): C, 66.54; H,6.76; N, 12.07.

PREPARATION EXAMPLE 1b

(1) Compound of Example 9b 10.0 mg

(2) Lactose 60.0 mg

(3) Corn starch 35.0 mg

(4) Gelatin 3.0 mg

(5) Magnesium stearate 2.0 mg

A mixture of 10.0 mg of the compound obtained in Example 9b, 60.0 mg oflactose and 35.0 mg of corn starch was granulated through a sieve of 1mm mesh, using 0.03 ml of a 10% aqueous solution of gelatin (containing3.0 mg of gelatin), after which it was dried at 40° C. and again sieved.The resulting granules were mixed with 2.0 mg of magnesium stearate,followed by compression. The resulting core tablets were coated with asugar coat, using an aqueous suspension of sucrose, titanium dioxide,talc and gum arabic. The coated tablets were polished with beeswax toyield finished coated tablets.

PREPARATION EXAMPLE 2b

(1) Compound of Example 9b 10.0 mg

(2) Lactose 70.0 mg

(3) Corn starch 50.0 mg

(4) Soluble starch 7.0 mg

(5) Magnesium stearate 3.0 mg

After 10.0 mg of the compound obtained in Example 9b and 3.0 mg ofmagnesium stearate were granulated using 0.07 ml of an aqueous solutionof soluble starch (containing 7.0 mg of soluble starch), the resultinggranules were dried and mixed with 70.0 mg of lactose and 50.0 mg ofcorn starch. The mixture was compressed to yield tablets.

PREPARATION EXAMPLE 3b

(1) Compound of Example 9b 5.0 mg

(2) Sodium chloride 20.0 mg

(3) Distilled water was added to reach a total volume of 2 ml.

5.0 mg of the compound obtained in Example 9b and 20.0 mg of sodiumchloride were dissolved in distilled water and diluted with water toreach a total volume of 2.0 ml. The resulting solution was filtered andaseptically packed in a 2 ml ampule. After sterilization, the ampule wassealed to yield a solution for injection.

EXPERIMENTAL EXAMPLE 1b

In the same manner as Experimental Example 1a, the effects of variousexample compounds on histamine-induced skin reactions in guinea pigswere examined. The results are shown in Table 3.

TABLE 3 Effects of Test Compounds on Histamine-induced Skin VascularPermeability Suppression (%) of histamine-induced skin vascularpermeability elevation, Compound oral administration at 3 mg/kg Example3b 94 Example 4b 92 Example 7b 89 Example 8b 74

EXPERIMENTAL EXAMPLE 2b

In the same manner as Experimental Example 2a, the percent suppressionof LTB₄-induced chemotactic reactions by various example compounds wascalculated. The results are shown in Table 4.

TABLE 4 Effects on LTB₄-induced Chemotactic Reaction in Guinea PigEosinophils Compound Suppression rate (%) Example 7b 26 Example 8b 57Example 10b 55 Example 11b 100

INDUSTRIAL APPLICABILITY

Compound (I) of the present invention, or a salt thereof, or a pro-drugthereof exhibits excellent anti-allergic activity, anti-histaminicactivity, anti-inflammatory activity, anti-PAF (platelet-activatingfactor) activity, eosinophil chemotaxis-inhibiting activity, and thelike, and can be safely used as an anti-allergic agent. Furthermore,Compound (I) of the present invention, or a salt thereof, or a pro-drugthereof exhibits an eosinophil chemotaxis-inhibiting activity as well asan anti-histaminic activity, and can be used to prevent or treatallergic diseases such as chronic urticaria and other forms of urticaria(e.g., acute urticaria), atopic dermatitis, allergic rhinitis, allergicconjunctivitis and hypersensitivity pneumonitis; dermal diseases(especially allergic dermal diseases) such as itching, herpeticdermatitis, eczematous dermatitis, contact dermatitis, prurigo andpsoriasis; respiratory diseases such as eosinophilic pneumonia (PIEsyndrome), chronic obstructive pulmonary disease (COPD), and asthma;etc.

What is claimed is:
 1. A compound represented by the formula:

wherein Ring A is a ring represented by the formula:

wherein R^(1a) is a hydrogen atom, a halogen atom, an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, an alkynyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an acyl group or a hydroxy group having a substituent; R^(1b) is a hydrogen atom, a halogen atom, an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, an alkynyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an acyl group or a hydroxy group optionally having a substituent; Ar¹ and Ar² are independently a phenyl group optionally having a substituent; Ring B is a ring represented by the formula:

wherein Z is a nitrogen atom or a methine group, Z¹ and Z² are each independently a linear C₁₋₄ alkylene group optionally having a substituent; X and Y, whether identical or not, are (i) a bond, (ii) an oxygen atom, (iii) S(O)p wherein p is an integer from 0 to 2, (iv) NR⁴ wherein R⁴ is a hydrogen atom or a lower alkyl group, or (v) a divalent linear lower hydrocarbon group which may have a substituent, and which may contain 1 to 3 hetero atoms; R² and R³, whether identical or not, are a hydrogen atom, a halogen atom, an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, an alkynyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an acyl group or a hydroxy group optionally having a substituent; R⁷ is a hydrogen atom, a hydroxy group which may be substituted by lower alkyl or a carboxyl group; or a salt thereof or a pro-drug thereof.
 2. A compound as claimed in claim 1 wherein Ar¹ and Ar² are independently a phenyl group which may be substituted by a halogen atom or C₁₋₆ alkyl.
 3. A compound as claimed in claim 1 wherein Ring B is a ring represented by the formula:

wherein Z is a nitrogen atom or a methine group, Z¹ and Z² are independently a linear C₁₋₄ alkylene group which may be substituted by a hydroxy group, an oxo group or a C₁₋₆ alkyl group.
 4. A compound as claimed in claim 1 wherein X is a bond, an oxygen atom or NH.
 5. A compound as claimed in claim 1 wherein Y is (i) a C₁₋₆ alkylene group, or a group represented by the formula: (ii) —(CH₂)p¹O—, (iii) —(CH₂)p¹NH—, (iv) —(CH₂)p¹S—, (v) —(CH₂)q¹CH(OH)(CH₂)q²O—, (vi) —(CH₂)q¹CH(OH)(CH₂)q²NH—, (vii) —(CH₂)q¹CH(OH)(CH₂)q²S—, (viii) —(CH₂)p¹CONH—, (ix) —COO (CH₂)p¹O—, (x) —COO(CH₂)p¹NH—, (xi) —COO(CH₂)p¹S—, (xii) —(CH₂)q¹O(CH₂)q²O—, (xiii) —(CH₂)q¹O(CH₂)q²NH— or (xiv) —(CH₂)q¹O(CH₂)q²S— wherein p¹ is an integer from 1 to 6, q¹ and q are independently an integer from 1 to
 3. 6. A compound as claimed in claim 1 wherein Y is a group represented by the formula: —(CH₂)m-Y¹—(CH₂)n-Y²— wherein Y¹ and Y² are independently a bond, an oxygen atom, S(O)p (p is an integer from 0 to 2), NR⁴ (R⁴ is a hydrogen atom or a lower alkyl group), a carbonyl group, a carbonyloxy group or a group represented by the formula:

wherein R⁵ and R⁶, whether identical or not, are a hydroxy group or a C₁₋₄ alkyl group; m and n are independently an integer from 0 to 4 (sum of m and n is not more than 6).
 7. A compound as claimed in claim 1 wherein R^(1a) is (1) a hydrogen atom, (2) a carboxyl group, (3) a C₁₋₆ alkoxy-carbonyl group, (4) a C₁₋₆ alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆ alkoxy-carbonyl and (iv) carbamoyl, or (5) a carbamoyl group which may be substituted by a C₁₋₆ alkyl group optionally having carboxyl or C₁₋₆ alkoxy-carbonyl.
 8. A compound represented by the formula:

wherein Ring A is a ring represented by the formula:

wherein R^(1b) is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii) C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkoxy-carbonyl; Ar¹ and Ar² are independently a phenyl group optionally having a substituent; Ring B is a ring represented by the formula:

wherein Z is a nitrogen atom or a methine group, Z¹ and Z² are each independently a linear C₁₋₄ alkylene group optionally having a substituent; X and Y, whether identical or not, are (i) a bond, (ii) an oxygen atom, (iii) S(O)p wherein p is an integer from 0 to 2, (iv) NR⁴ wherein R⁴ is a hydrogen atom or a lower alkyl group, or (v) a divalent linear lower hydrocarbon group which may have a substituent, and which may contain 1 to 3 hetero atoms; R² and R³, whether identical or not, are a hydrogen atom, a halogen atom, an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, an alkynyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an acyl group or a hydroxy group optionally having a substituent; R⁷ is a hydrogen atom, a hydroxy group which may be substituted by lower alkyl or a carboxyl group; or a salt thereof or a pro-drug thereof.
 9. A compound as claimed in claim 1 wherein R² and R³ are a hydrogen atom.
 10. A compound as claimed in claim 1 wherein R⁷ is a hydrogen atom or a hydroxy group.
 11. A compound as claimed in claim 1 wherein Ar¹ and Ar² are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula:

X is a bond or an oxygen atom; Y is a group represented by the formula: —(CH₂)m-Y³—(CH₂)n-Y⁴—  wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and m and n are independently an integer from 0 to 6 (sum of m and n is not more than 6); R^(1a) is (1) a hydrogen atom, (2) a carboxyl group, (3) a C₁₋₆ alkoxy-carbonyl group, (4) a C₁₋₆ alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆ alkoxy-carbonyl and (iv) carbamoyl, or (5) a carbamoyl group which may be substituted by a C₁₋₆ alkyl group optionally having carboxyl or C₁₋₆ alkoxy-carbonyl; R^(1b) is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii) C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkoxy-carbonyl; R², R³ and R⁷ are a hydrogen atom.
 12. A compound represented by the formula:

wherein the symbols have the same definitions as those shown in claim 1, or a salt thereof.
 13. A compound as claimed in claim 12 wherein Ar¹ and Ar² are independently a phenyl group which may be substituted: Ring B is a ring represented by the formula:

X is a bond or an oxygen atom; Y is a group represented by the formula: —(CH₂)m ¹-Y³—(CH₂)n ¹-Y⁴— wherein Y³ is a bond or —CH(OH)—, Y⁴ is an oxygen atom, S or NH, and m¹ and n¹ are independently an integer from 0 to 4 (sum of m¹ and n¹ is not more than 6); R^(1a) is (1) a hydrogen atom, (2) a carboxyl group, (3) a C₁₋₆ alkoxy-carbonyl group, (4) a C₁₋₆ alkyl group which may be substituted by a group selected from the group consisting of (i) cyano, (ii) carboxyl, (iii) C₁₋₆ alkoxy-carbonyl and (iv) carbamoyl, or (5) a carbamoyl group which may be substituted by a C₁₋₆ alkyl group optionally having carboxyl or C₁₋₆ alkoxy-carbonyl; and R², R³ and R⁷ are a hydrogen atom.
 14. {circle around (1)} 6-[6-[4-(diphenylmethoxy)piperidino]hexyloxy][1,2,4]triazolo[4,3-b]pyridazine, {circle around (2)} 6-[6-[4-(diphenylmethoxy)piperidino]hexylamino][1,2,4]triazolo[4,3-b]pyridazine, {circle around (3)} 3-tert-butyl-6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazine, {circle around (4)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic acid, or a salt thereof.
 15. A compound represented by the formula:

wherein the symbols have the same definitions as those shown in claim 1, or a salt thereof.
 16. A compound as claimed in claim 15 wherein the partial structural formula:

represents the formula:

provided that R^(1b) is a hydrogen atom.
 17. A compound as claimed in claim 15 wherein Ar¹ and Ar² are independently a phenyl group which may be substituted; Ring B is a ring represented by the formula:

X is an oxygen atom; Y is a group represented by the formula: —(CH₂)w-Y⁵— wherein w is an integer from 1 to 6, and Y⁵ is an oxygen atom or NH; R^(1b) is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group which may be substituted by a group selected from the group consisting of (i) carboxyl, (ii) C₁₋₆ alkoxy-carbonyl, (iii) C₁₋₆ alkyl-carbonyloxy and (iv) C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkoxy-carbonyl; and R², R³ and R⁷ are a hydrogen atom.
 18. {circle around (1)} 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, {circle around (2)} ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate, {circle around (3)} 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionic acid, {circle around (4)} pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate, {circle around (5)} pivaloyloxymethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate, or a salt thereof.
 19. A method for producing a compound as claimed in claim 1, which comprises reacting a compound represented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the same meanings as defined in claim 1, or a salt thereof, with a compound represented by the formula:

wherein Q² represents a leaving group; the other symbols have the same meanings as defined in claim 1, or a salt thereof.
 20. A method for producing a compound as claimed in claim 12, which comprises reacting a compound represented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the same meanings as defined in claim 1, or a salt thereof, with a compound represented by the formula:

wherein Q² represents a leaving group; the other symbols have the same meanings as defined in claim 1, or a salt thereof.
 21. A method for producing a compound as claimed in claim 15, which comprises reacting a compound represented by the formula:

wherein Q¹ represents a leaving group; the other symbols have the same meanings as defined in claim 15, or a salt thereof, with a compound represented by the formula:

wherein Q² represents a leaving group; the other symbols have the same meanings as defined in claim 15, or a salt thereof.
 22. A pharmaceutical composition comprising: a compound as claimed in claim 1; and a pharmaceutically acceptable excipient, binder, disintegrating agent, additive, solvent or carrier.
 23. A pharmaceutical composition as claimed in claim 22 which is an anti-histaminic and/or eosinophil chemotaxis-inhibiting agent.
 24. A pharmaceutical composition as claimed in claim 22 which is an anti-allergic agent.
 25. A pharmaceutical composition as claimed in claim 22 which is an agent for preventing or treating asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopic dermatitis.
 26. A method for suppressing histamine, eosinophil chemotaxis or a combination thereof comprising administering an effective amount of a compound as claimed in claim 1 to mammals.
 27. A method for treating allergic diseases comprising administering an effective amount of a compound as claimed in claim 1 to mammals.
 28. A method for treating asthma, allergic conjunctivitis, allergic rhinitis, chronic urticaria or atopic dermatitis which comprises administering an effective amount of a compound as claimed in claim 1 to mammals. 